Resorcinol derivatives

ABSTRACT

The present invention relates to the use of certain resorcinol derivatives as skin lightening agents.

This application is a continuation-in-part of U.S. application Ser. No.09/526,287, filed Mar. 15, 2000, which claims priority from U.S.provisional application Ser. No. 60/125,534, filed Mar. 22, 1999.

FIELD OF THE INVENTION

The present invention relates to the use of certain resorcinolderivatives as skin lightening agents.

BACKGROUND OF THE INVENTION

The terms “lightening agent” and “depigmentation agent” are usedinterchangeably throughout this document.

Skin color in humans arises from a complex series of cellular processesthat are carried out within a unique population of cells calledmelanocytes. Melanocytes are located in the lower part of the epidermis,and their function is to synthesize a pigment, melanin, which protectsthe body from the damaging effects of ultraviolet radiation.

When skin is exposed to ultraviolet radiation, such as that contained insunlight, melanocytes increase their synthesis of melanin. Melanin isdeposited in melanosomes, which are vesicles found within the cell. Themelanosomes are extruded from the cell and carried to the surface of theskin by keratinocytes, which internalize the melanin-containingmelanosomes. The end result is that the visible layers of the skinexhibit a brown color typically known as a “tan”. The darkness of thecolor observed in the skin is proportionate to the amount of melaninsynthesized by melanocytes and transferred to the keratinocytes.

The mechanism by which skin pigmentation is formed, melanogenesis, isparticularly complex and schematically involves the following mainsteps: Tyrosine→L-Dopa→Dopaquinone→Dopachrome→Melanins. The first tworeactions in this series are catalyzed by the enzyme tyrosinase. Theactivity of tyrosinase is promoted by the action of α-melanocytestimulating hormone or UV rays to have melanin eventually formed aschromatism in the skin. It is well established that a substance has adepigmenting effect if it acts directly on the vitality of the epidermalmelanocytes where melanogenesis normally occurs and/or if it interfereswith one of the stages in melanin biosynthesis. The active compoundsthat are employed in the various methods and compositions of thisinvention inhibit tyrosinase and thus inhibit or decrease melaninbiosynthesis.

There is a strong demand for agents that enable acquired depositionsites, such as spots or freckles, to be restored to a normal skin color.For this purpose, a variety of agents and methods have been developedand put on the market. Examples of such methods are (a) a method whereinvitamin C (L-ascorbic acid) having good reducing ability is administeredorally in large amounts, (b) a method wherein glutathione isadministered parenterally; (c) a method wherein a peroxide, such ashydrogen peroxide, zinc peroxide, sodium peroxide and the like, which isbelieved to have the bleaching action of melamine, is administered: and(d) a method wherein vitamin C or cysteine is administered topically inthe form of an ointment, cream, lotion or the like. Vitamin C has aproblem with respect to stability and becomes so unstable inwater-containing systems that they will cause changes in odor and color.Thiol compounds such as glutathione and cysteine do not exhibit asatisfactory depigmental effect since the development of the effect isvery slow.

The substances in widest use at the present time as depigmentors are, inparticular, hydroquinone and its derivatives, particularly its etherssuch as hydroquinone monomethyl ether. These compounds, while effective,are known to produce side effects that can be dangerous. Hydroquinone,use of which is limited to a concentration of 2%, is both irritating andcytotoxic to the melanocyte.

U.S. Pat. No. 4,526,179 refers to certain hydroquinone fatty esters thathave good activity and are less irritating and more stable thanhydroquinone.

Japanese Patent Application No. 27909/86 refers to other hydroquinonederivatives that do not have the drawbacks of hydroquinone but that haverelatively poor efficacy.

U.S. Pat. No. 5,449,518 refers to 2,5-dihydoxyphenyl carboxylic acidderivatives as skin depigmentation agents.

European Patent Application EP 341,664A1 refers to certain resorcinolderivatives as tyrosinase inhibitors and skin depigmentation agents.

PCT International Publication WO 99/15148 refers to certain resorcinolderivatives as tyrosinase inhibitors and skin depigmentation agents.

The use of topical depigmention agents that have good efficacy and areharmless is particularly desirable for treating the following: regionalhyperpigmentation caused by melanocytic hyperactivity, such asidiopathic melasma occurring either during pregnancy (mask of pregnancyor chloasma) or secondary to estrogen-progesterone contraception; localhyperpigmentation caused by benign melanocytic hyperactivity andproliferation such as lentigo senilis or liver spots; accidentalhyperpigmentation such as post-lesional photosensitization and scarring;and certain forms of leukoderma such as vitiligo where, if the injuredskin cannot be repigmented, the residual zones of normal skin aredepigmented to impart a homogeneous white color to the entire skin.

SUMMARY OF INVENTION

The resorcinol derivatives of formula I, which are defined below andused in the various methods and compositions of this invention, areuseful in the treatment of the foregoing dermatological conditions aswell as other dermatological conditions, some of which are referred tolater in this document, for which the subject being treated desires, formedicinal or cosmetic purposes, to lighten or reduce the pigmentation ofthe skin affected by the condition.

The resorcinol derivatives of formula I are also useful for thetreatment of inflammatory disorders such as psoriasis, dermatitis andacne, and for the treatment of dandruff.

The invention thus provides a compound of formula l:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is a (C₃-C₈)cycloalkyl ring or (C₅-C₈)cycloalkenyl ring, whereineither the cycloalkyl ring or cycloalkenyl ring is substituted by one tothree substituents independently selected from the group consisting ofcyano; halo; (C₁-C₆)alkyl; aryl; (C₂-C₉)heterocycloalkyl;(C₂-C₉)heteroaryl; aryl(C₁-C₆)alkyl-; ═O; ═CHO(C₁-C₆)alkyl; amino;hydroxy; (C₁-C₆)alkoxy; aryl(C₁-C₆)alkoxy-; (C₁-C₆)acyl;(C₁-C₆)alkylamino-; aryl(C₁-C₆)alkylamino-; amino(C₁-C₆)alkyl-;(C₁-C₆)alkoxy-CO—NH—; (C₁-C₆)alkylamino-CO—; (C₂-C₆)alkenyl;(C₂-C₆)alkynyl; hydroxy(C₁-C₆)alkyl-; (C₁-C₆)alkoxy(C₁-C₆)alkyl-;(C₁-C₆)acyloxy(C₁-C₆)alkyl-; nitro; cyano(C₁-C₆)alkyl-;halo(C₁-C₆)alkyl-; nitro(C₁-C₆)alkyl-; trifluoromethyl;trifluoromethyl(C₁-C₆)alkyl-; (C₁-C₆)acylamino-;(C₁-C₆)acylamino(C₁-C₆)alkyl-; (C₁-C₆)alkoxy(C₁-C₆)acylamino-;amino(C₁-C₆)acyl-; amino(C₁-C₆)acyl(C₁-C₆)alkyl-;(C₁-C₆)alkylamino(C₁-C₆)acyl-; ((C₁-C₆) alkyl)₂amino(C₁-C₆)acyl-;—CO₂R²; —(C₁-C₆)alkyl-CO₂R²; —C(O)N(R²)₂; —(C₁-C₆)alkyl-C(O)N(R²)₂;R²ON═; R²ON═(C₁-C₆)alkyl-; R²ON═CR²(C₁-C₆)alkyl-; —NR²(OR²);—(C₁-C₆)alkyl-NR²(OR²); —C(O)(NR²R²); —(C₁-C₆)alkyl-C(O)(NR²OR²);—S(O)_(m)R²; wherein each R² is independently selected from hydrogen,(C₁-C₆)alkyl, aryl, or aryl(C₁-C₆)alkyl-; R³C(O)O—, wherein R³ is(C₁-C₆)alkyl, aryl, or aryl(C₁-C₆)alkyl-; R³C(O)O—(C₁-C₆)alkyl-;R⁴R⁵N—C(O)—O—; R⁴R⁵NS(O)₂—; R⁴R⁵NS(O)₂(C₁-C₆)alkyl-; R⁴S(O)₂R⁵N—;R⁴S(O)₂R⁵N(C₁-C₆)alkyl-; wherein m is 0, 1 or 2, and R⁴ and R⁵ are eachindependently selected from hydrogen or (C₁-C₆)alkyl; —C(═NR⁶)(N(R⁴)₂);or —(C₁-C₆)alkyl-C(═NR⁶)(N(R⁴)₂) wherein R⁶ represents OR² or R² whereinR² is defined as above;

with the proviso that the cycloalkenyl ring is not aromatic;

with the proviso that R¹ must be substituted by at least one ofR³C(O)O—, R³C(O)O—(C₁-C₆)alkyl-, R²ON═, R²ON═(C₁-C₆)alkyl-, R²ON═CR²(C₁-C₆)alkyl-, —NR²(OR²), R⁴R⁵NS(O)₂—, R⁴R⁵NS(O)₂(C₁-C₆)alkyl-,R⁴S(O)₂R⁵N—, or R⁴S(O)₂R⁵N(C₁-C₆)alkyl-;

with the proviso that when R¹ is only substituted by one of R²ON═, thenR² cannot be hydrogen.

Where R¹ is a cyclohexyl or cyclohexenyl ring, the ring is preferablysubstituted at the 3- or 4-position, and more preferably at the4-position.

Where R¹ is a cyclopentyl or cyclopentenyl ring, the ring is preferablysubstituted at the 3-position.

In a preferred embodiment, R¹ is monosubstituted.

In a further preferred embodiment, R¹ is disubstituted.

In a preferred embodiment, R¹ is substituted by at least one of R³C(O)O—or R³C(O)O—(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ is substituted by at least one ofR³C(O)O—.

In a further preferred embodiment, R¹ is substituted by at least one ofR³C(O)O—(C₁-₆)alkyl-.

In a further preferred embodiment, R¹ is substituted by at least one ofR² ON═, R²ON═(C₁-C₆)alkyl-, or R²ON═CR²(C₁-C₆)alkyl-; with the provisothat when R¹ is only substituted by one of R²ON═, then R² cannot behydrogen.

In a further preferred embodiment, R¹ is substituted by at least one ofR²ON═, with the proviso that when R¹ is only substituted by one ofR²ON═, then R² cannot be hydrogen.

In a further preferred embodiment, R¹ is substituted by at least one of—NR²(OR²).

In a further preferred embodiment, R¹ is substituted by at least one ofR⁴R⁵NS(O)₂—, R⁴R⁵NS(O)₂(C₁-C₆)alkyl-, R⁴S(O)₂R⁵N—, orR⁴S(O)₂R⁵N(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ is substituted by at least one ofR⁴S(O)₂R⁵N—.

In a further preferred embodiment, R¹ is substituted by at least one ofR4S(O)₂R⁵N(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ is a (C₃-C₈)cycloalkyl ring or(C₅-C₈)cycloalkenyl ring, wherein either the cycloalkyl ring orcycloalkenyl ring is substituted by one of R³C(O)O—,R³C(O)O—(C₁-C₆)alkyl-, R²ON═, R²ON═(C₁-C₆)alkyl-, R²ON═CR²(C₁-C₆)alkyl-,—NR²(OR²), R⁴R⁵NS(O)₂—, R⁴R⁵NS(O)₂(C₁-C₆)alkyl-, R⁴S(O)₂R⁵N—, orR⁴S(O)₂R⁵N(C₁-C₆)alkyl-; wherein R², R³, R⁴ and R⁵ are as defined above;

with the proviso that the cycloalkenyl ring is not aromatic;

and with the proviso that when R¹ is substituted by R²ON═, then R²cannot be hydrogen.

In a further preferred embodiment, R¹ is a (C₃-C₈)cycloalkyl ring or(C₅-C₈)cycloalkenyl ring, wherein either the cycloalkyl ring orcycloalkenyl ring is substituted by one of R³C(O)O—,R³C(O)O—(C₁-C₆)alkyl-, R²ON═, or R⁴S(O)₂R⁵N—; wherein R², R³, R⁴ and R⁵are as defined above;

with the proviso that the cycloalkenyl ring is not aromatic;

and with the proviso that when R¹ is substituted by R²ON═, then R²cannot be hydrogen.

In a further preferred embodiment, R¹ is substituted by R³C(O)O— orR³C(O)O—(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ is substituted by R³C(O)O—.

In a further preferred embodiment, R¹ is substituted byR³C(O)O—(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ is substituted by R²ON═,R²ON═(C₁-C₆)alkyl-, or R²ON═CR²(C₁-C₆)alkyl-, with the proviso that whenR¹ is substituted by R²ON═, then R² cannot be hydrogen.

In a further preferred embodiment, R¹ is substituted by R²ON═, where R²cannot be hydrogen.

In a further preferred embodiment, R¹ is substituted by —NR²(OR²).

In a further preferred embodiment, R¹ is substituted by R⁴R⁵NS(O)₂—,R⁴R⁵NS(O)₂(C₁-C₆)alkyl-, R⁴S(O)₂R⁵N— or R⁴S(O)₂R⁵N(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ is substituted by R⁴S(O)₂R⁵N—.

In a further preferred embodiment, R¹ is substituted byR⁴S(O)₂R⁵N(C₁-C₆) alkyl-.

The (C₂-C₉)heterocycloalkyl substituent, when present on R¹, ispreferably a group of the formula:

wherein m is as defined above, and

Z is CH₂, NR², OS, SO, or SO₂.

For any of the aforementioned compounds of the present invention, R¹ ispreferably a group of the formula:

which is substituted as described above for R¹;

wherein n is 0, 1, or 2;

wherein the dashed line indicates an optional double bond at thatposition.

In a preferred embodiment, n is 0 or 1.

In a further preferred embodiment, n is 0; and the dashed linerepresents a double bond at that position.

In a further preferred embodiment, n is 1.

In a further preferred embodiment, R¹ is substituted by ═O, ═NOH, CH₂OH,

or a combination thereof.

In a further preferred embodiment, n is 0; R¹ is substituted by ═NOH;and the dashed line represents a double bond at that position.

In further preferred embodiment, n is 1; and R¹ is substituted by ═O,═NOH, CH₂OH, or

or a combination thereof.

The invention further provides a compound selected from the groupconsisting of:

O-Benzyl-4-(2,4-dihydroxyphenyl)cyclohexanone oxime;

(±)-N-[3-(2,4-Dihydroxyphenyl)cyclohexyl]methanesulfonamide;

(±)-O-Methyl-3-(2,4-dihydroxyphenyl)cyclohexanone oxime;

(±)-O-Benzyl-3-(2,4-dihydroxyphenyl)cyclohexanone oxime;

and a pharmaceutically acceptable salt thereof.

The invention further provides a compound selected from the groupconsisting of:

O-Methyl-4-(2,4-dihydroxyphenyl)cyclohexanone oxime;

(±)-4-[3-(Hydroxyamino)cyclohexyl]-1,3-benzenediol;

cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-1-butanesulfonamide;

trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]methanesulfonamide;

cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]methanesulfonamide;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl) 4-(dimethylamino)benzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-tert-butyl benzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-fluorobenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-trifluoromethylbenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-methoxybenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-methylbenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-chlorobenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 3,4-dimethylbenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 3,4-dichlorobenzoate;

[4-(2,4-Dihydroxyphenyl)cyclohexyl]methyl propionate;

cis/trans-4-[4-(hydroxyamino)cyclohexyl]-1,3-benzenediol;

trans-4-[4-(methoxyamino)cyclohexyl]-1,3-benzenediol;

and a pharmaceutically acceptable salt thereof.

The present invention further provides a topical pharmaceuticalcomposition for lightening skin or reducing the pigmentation of skin ina human, comprising a pharmaceutically acceptable carrier, and askin-lightening or pigmentation-reducing amount of a compound of formulaI:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is a (C₃-C₈)cycloalkyl ring or (C₅-C₈)cycloalkenyl ring, whereineither the cycloalkyl ring or cycloalkenyl ring is substituted by one tothree substituents independently selected from the group consisting ofcyano; halo; (C₁-C₆)alkyl; aryl; (C₂-C₉)heterocycloalkyl;(C₂-C₉)heteroaryl; aryl(C₁-C₆)alkyl-; ═O; ═CHO(C₁-C₆)alkyl; amino;hydroxy; (C₁-C₆)alkoxy; aryl(C₁-C₆)alkoxy-; (C₁-C₆)acyl;(C₁-C₆)alkylamino-; aryl(C₁-C₆)alkylamino-; amino(C₁-C₆)alkyl-;(C₁-C₆)alkoxy-CO—NH—; (C₁-C₆)alkylamino-CO—; (C₂-C₆)alkenyl;(C₂-C₆)alkynyl; hydroxy(C₁-C₆)alkyl-; (C₁-C₆)alkoxy(C₁-C₆)alkyl-;(C₁-C₆)acyloxy(C₁-C₆)alkyl-; nitro; cyano(C₁-C₆)alkyl-;halo(C₁-C₆)alkyl-; nitro(C₁-C₆)alkyl-; trifluoromethyl;trifluoromethyl(C₁-C₆)alkyl-; (C₁-C₆)acylamino-;(C₁-C₆)acylamino(C₁-C₆)alkyl-; (C₁-C₆)alkoxy(C₁-C₆)acylamino-;amino(C₁-C₆)acyl-; amino(C₁-C₆)acyl(C₁-C₆)alkyl-;(C₁-C₆)alkylamino(C₁-C₆)acyl-; ((C₁-C₆) alkyl)₂amino(C₁-C₆)acyl-;—CO₂R²; —(C₁-C₆)alkyl-CO₂R²; —C(O)N(R²)₂; —(C₁-C₆)alkyl-C(O)N(R²)₂;R²ON═; R²ON═(C₁-C₆)alkyl-; R²ON═CR²(C₁-C₆)alkyl-; —NR²(OR²);—(C₁-C₆)alkyl-NR²(OR²); C(O)(NR²OR²); —(C₁-C₆)alkyl-C(O)(NR²OR²);—S(O)_(m)R²; wherein each R² is independently selected from hydrogen,(C₁-C₆)alkyl, aryl, or aryl(C₁-C₆)alkyl-; R³C(O)O—, wherein R³ is(C₁-C₆)alkyl, aryl, or aryl(C₁-C₆)alkyl-; R³C(O)O—(C₁-C₆)alkyl-;R⁴R⁵N—C(O)—O—; R⁴R⁵NS(O)₂—; R⁴R⁵NS(O)₂(C₁-C₆)alkyl-; R⁴S(O)₂R⁵N—;R⁴S(O)₂R⁵N(C₁-C₆)alkyl-; wherein m is 0, 1 or 2, and R⁴ and R⁵ are eachindependently selected from hydrogen or (C₁-C₆)alkyl; —C(═NR⁶)(N(R⁴)₂);or —(C₁-C₆)alkyl-C(═NR⁶)(N(R⁴)₂) wherein R⁶ represents OR² or R² whereinR² is defined as above;

with the proviso that the cycloalkenyl ring is not aromatic;

with the proviso that R¹ must be substituted by at least one ofR³C(O)O—, R³C(O)O—(C₁-C₆)alkyl-, R²ON═, R²ON═(C₁-C₆)alkyl-,R²ON═CR²(C₁-C₆)alkyl-, —NR²(OR²), R⁴R⁵NS(O)₂—, R⁴R⁵NS(O)₂(C₁-C₆)alkyl-,R⁴S(O)₂R⁵N—, or R⁴S(O)₂R⁵N(C₁-C₆)alkyl-.

Where R¹ is a cyclohexyl or cyclohexenyl ring, the ring is preferablysubstituted at the 3- or 4-position, and more preferably at the4-position.

Where R¹ is a cyclopentyl or cyclopentenyl ring, the ring is preferablysubstituted at the 3-position.

In a preferred embodiment, R¹ is monosubstituted.

In a further preferred embodiment, R¹ is disubstituted.

In a preferred embodiment, R¹ is substituted by at least one of R³C(O)O—or R³C(O)O—(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ is substituted by at least one ofR³C(O)O—.

In a further preferred embodiment, R¹ is substituted by at least one ofR³C(O)O—(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ is substituted by at least one ofR²ON═, R²ON═(C₁-C₆)alkyl-, or R²ON═CR²(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ is substituted by at least one ofR²ON═.

In a further preferred embodiment, R¹ is substituted by at least one of—NR²(OR²).

In a further preferred embodiment, R¹ is substituted by at least one ofR⁴R⁵NS(O)₂—, R⁴R⁵NS(O)₂(C₁-C₆)alkyl-, R⁴S(O)₂R⁵N—, orR⁴S(O)₂R⁵N(C₁-C₆)alkyl-.

In a further preferred embodiment, R₁ is substituted by at least one ofR⁴S(O)₂R⁵N—.

In a further preferred embodiment, R₁ is substituted by at least one ofR⁴S(O)₂R⁵N(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ is a (C₃-C₈)cycloalkyl ring or(C₅-C₈)cycloalkenyl ring, wherein either the cycloalkyl ring orcycloalkenyl ring is substituted by R³C(O)O—, R³C(O)O—(C₁-C₆)alkyl-,R²ON═, R²ON═(C₁-C₆)alkyl-, R²ON═CR²(C₁-C₆)alkyl-, —NR²(OR²),R⁴R⁵NS(O)₂—, R⁴R⁵NS(O)₂(C₁-C₆)alkyl-, R⁴S(O)₂R⁵N—, orR⁴S(O)₂R⁵N(C₁-C₆)alkyl-; wherein R², R³, R⁴ and R⁵ are as defined above;

with the proviso that the cycloalkenyl ring is not aromatic.

In a further preferred embodiment, R¹ is a (C₃-C₈)cycloalkyl ring or(C₅-C₈)cycloalkenyl ring, wherein either the cycloalkyl ring orcycloalkenyl ring is substituted by one of R³C(O)O—,R³C(O)O—(C₁-C₆)alkyl-, R²ON═, or R⁴S(O)₂R⁵N—; wherein R², R³, R⁴ and R⁵are as defined above;

with the proviso that the cycloalkenyl ring is not aromatic.

In a preferred embodiment, R¹ is substituted by R³C(O)O— orR³C(O)O—(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ is substituted by R³C(O)O—.

In a further preferred embodiment, R¹ is substituted byR³C(O)O—(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ is substituted by R²ON═,R²ON═(C₁-C₆)alkyl-, or R²ON═CR²(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ is substituted by R²ON═.

In a further preferred embodiment, R¹ is substituted by —NR²(OR²).

In a further preferred embodiment, R¹ is substituted by R⁴R⁵NS(O)₂—,R⁴R⁵NS(O)₂(C₁-C₆)alkyl-, R⁴S(O)₂R⁵N—, or R⁴S(O)₂R⁵N(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ is substituted by R⁴S(O)₂R⁵N—.

In a further preferred embodiment, R¹ is substituted byR⁴S(O)₂R⁵N(C₁-C₆)alkyl-.

The (C₂-C₉)heterocycloalkyl substituent, when present on R¹ of thecompound of formula I, is preferably a group of the formula:

wherein m is as defined above, and

Z is CH₂, NR², O, S, SO, or SO_(2.)

For any of the aforementioned compositions of the present invention, R¹of the compound of formula I is preferably a group of the formula:

which is substituted as described above for R¹;

wherein n is 0, 1, or 2;

wherein the dashed line indicates an optional double bond at thatposition.

In a further preferred embodiment, n is 0 or 1.

In a further preferred embodiment, n is 0; and the dashed linerepresents a double bond at that position.

In a further preferred embodiment, n is 1.

In a further preferred embodiment, R¹ is substituted by ═O, ═NOH, CH₂OHor

or a combination thereof.

In a further preferred embodiment, n is 0; R¹ is substituted by ═NOH;and the dashed line represents a double bond at that position.

In further preferred embodiment, n is 1; and R¹ is substituted by ═O,═NOH, CH₂OH, or

or a combination thereof.

The present invention further provides a topical pharmaceuticalcomposition for lightening skin or reducing the pigmentation of skin ina human, comprising a pharmaceutically acceptable carrier, and askin-lightening or pigmentation-reducing effective amount of a compoundselected from the group consisting of:

4-(2,4-Dihydroxyphenyl)cyclohexanone oxime;

O-Methyl-4-(2,4-dihydroxyphenyl)cyclohexanone oxime;

O-Benzyl-4-(2,4-dihydroxyphenyl)cyclohexanone oxime;

3-(2,4-Dihydroxyphenyl)-2-cyclohexen-1-one oxime;

(±)-3-(2,4-Dihydroxyphenyl)cyclohexanone oxime;

(±)-N-[3-(2,4-Dihydroxyphenyl)cyclohexyl]methanesulfonamide;

(±)-4-[3-(Hydroxyamino)cyclohexyl]-1,3-benzenediol;

(±)-O-Methyl-3-(2,4-dihydroxyphenyl)cyclohexanone oxime;

(±)-O-Benzyl-3-(2,4-dihydroxyphenyl)cyclohexanone oxime;

3-(2,4-Dihydroxyphenyl)-2-cyclopentenone oxime;

(±)-3-(2,4-Dihydroxyphenyl)cyclopentanone oxime;

and a pharmaceutically acceptable salt thereof.

The present invention further provides a topical pharmaceuticalcomposition for lightening skin or reducing the pigmentation of skin ina human, comprising a pharmaceutically acceptable carrier, and askin-lightening or pigmentation-reducing effective amount of a compoundselected from the group consisting of:

cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-1-butanesulfonamide;

trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]methanesulfonamide;

cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]methanesulfonamide;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl) 4-(dimethylamino)benzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-tert-butylbenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-fluorobenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-trifluoromethylbenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-methoxybenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-methylbenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-chlorobenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 3,4-dimethylbenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 3,4-dichlorobenzoate;

[4-(2,4-Dihydroxyphenyl)cyclohexyl]methyl propionate;

cis/trans-4-[4-(hydroxyamino)cyclohexyl]-1,3-benzenediol;

trans-4-[4-(methoxyamino)cyclohexyl]-1,3-benzenediol;

and a pharmaceutically acceptable salt thereof.

In a further preferred embodiment, the skin-lightening orpigmentation-reducing effective amount of a compound of formula I of thepharmaceutical composition of the present invention is atyrosinase-inhibiting effective amount of the compound.

The present invention further provides a topical pharmaceuticalcomposition for inhibiting tyrosinase in a human, comprising apharmaceutically acceptable carrier, and a tyrosinase-inhibitingeffective amount of a compound selected from among the compounds of anyof the aforementioned pharmaceutical compositions of the presentinvention.

The present invention further provides a method of lightening skin orreducing the pigmentation of skin in a human, comprising administeringto said human a skin-lightening or skin pigmentation-reducing effectiveamount of a compound of formula l:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is a (C₃-C₈)cycloalkyl ring or (C₅-C₈)cycloalkenyl ring, whereineither the cycloalkyl ring or cycloalkenyl ring is substituted by one tothree substituents independently selected from the group consisting ofcyano; halo; (C₁-C₆)alkyl; aryl; (C₂-C₉)heterocycloalkyl;(C₂-C₉)heteroaryl; aryl(C₁-C₆)alkyl-; ═O; ═CHO(C₁-C₆)alkyl; amino;hydroxy; (C₁-C₆)alkoxy; aryl(C₁-C₆)alkoxy-; (C₁-C₆)acyl;(C₁-C₆)alkylamino-; aryl(C₁-C₆)alkylamino-; amino(C₁-C₆)alkyl-;(C₁-C₆)alkoxy-CO—NH—; (C₁-C₆)alkylamino-CO—; (C₂-C₆)alkenyl;(C₂-C₆)alkynyl; hydroxy(C₁-C₆)alkyl-; (C₁-C₆)alkoxy(C₁-C₆)alkyl-;(C₁-C₆)acyloxy(C₁-C₆)alkyl-; nitro; cyano(C₁-C₆)alkyl-;halo(C₁-C₆)alkyl-; nitro(C₁-C₆)alkyl-; trifluoromethyl;trifluoromethyl(C₁-C₆)alkyl-; (C₁-C₆)acylamino-;(C₁-C₆)acylamino(C₁-C₆)alkyl-; (C₁-C₆)alkoxy(C₁-C₆)acylamino-;amino(C₁-C₆)acyl-; amino(C₁-C₆)acyl(C₁-C₆)alkyl-;(C₁-C₆)alkylamino(C₁-C₆)acyl-; ((C₁-C₆) alkyl)₂amino(C₁-C₆)acyl-;—CO₂R²; —(C₁-C₆)alkyl-CO₂R²; —C(O)N(R²)₂; —(C₁-C₆)alkyl-C(O)N(R²)₂;R²ON═; R²ON═(C₁-C₆)alkyl-; R²ON═CR²(C₁-C₆)alkyl-; —NR²(OR²);—(C₁-C₆)alkyl-NR²(OR²); —C(O)(NR²OR²); —(C₁-C₆)alkyl-C(O)(NR²OR²);—S(O)_(m)R²; wherein each R2 is independently selected from hydrogen,(C₁-C₆)alkyl, aryl, or aryl(C₁-C₆)alkyl-; R³C(O)O—, wherein R³ is(C₁-C₆)alkyl, aryl, or aryl(C₁-C₆)alkyl-; R³C(O)O—(C₁-C₆)alkyl-;R⁴R⁵N—C(O)—O—; R⁴R⁵NS(O)₂—; R⁴R⁵NS(O)₂(C₁-C₆)alkyl-; R⁴S(O)₂R⁵N—;R⁴S(O)₂R⁵N(C₁-C₆)alkyl-; wherein m is 0, 1 or 2, and R⁴ and R⁵ are eachindependently selected from hydrogen or (C₁-C₆)alkyl; —C(═NR⁶)(N(R⁴)₂);or —(C₁-C₆)alkyl-C(═NR⁶)(N(R⁴)₂) wherein R⁶ represents OR² or R² whereinR² is defined as above;

with the proviso that the cycloalkenyl ring is not aromatic;

with the proviso that when R¹ is a (C₅-C₈)cycloalkyl ring, or when R¹ isa (C₅-C₈)cycloalkenyl ring having the following structure:

wherein n is 0, 1, 2 or 3, where such (C₅-C₈)cycloalkyl ring or(C₅-C₈)cycloalkenyl ring is substituted by hydroxy, (C₁-C₆)alkoxy-,aryl(C₁-C₆)alkoxy-, —OC(O)(C₁-C₆)alkyl, —OC(O)aryl(C₁-C₆)alkyl,—OC(O)phenyl, halo, (C₁-C₆)alkyl-, aryl(C₁-C₆)alkyl-, —SH,—S(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl-S—, —NH₂, —NH(C₁-C₆)alkyl, oraryl(C₁-C₆)alkyl-HN—; then the (C₅-C₈)cycloalkyl ring or the(C₅-C₈)cycloalkenyl ring must be di- or tri-substituted.

Where R¹ is a cyclohexyl or cyclohexenyl ring, the ring is preferablysubstituted at the 3- or 4-position, and more preferably at the4-position.

Where R¹ is a cyclopentyl or cyclopentenyl ring, the ring is preferablysubstituted at the 3-position.

In a preferred embodiment, R¹ is monosubstituted.

In a further preferred embodiment, R¹ is disubstituted.

In a preferred embodiment, R¹ of the compound of the method issubstituted by at least one of R³C(O)O—, R³C(O)O—(C₁-C₆)alkyl-, R²ON═,R²ON═(C₁-C₆)alkyl-, R²ON═CR²(C₁-C₆)alkyl-, —NR²(OR²), R⁴R⁵NS(O)₂—,R⁴R⁵NS(O)₂(C₁-C₆)alkyl-, R⁴S(O)₂R⁵N—, or R⁴S(O)₂R⁵N(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ of the compound of the method issubstituted by at least one of R³C(O)O— or R³C(O)O—(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ is substituted by at least one ofR³C(O)O—.

In a further preferred embodiment, R¹ is substituted by at least one ofR³C(O)O—(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ of the compound of the method issubstituted by at least one of R²ON═, R²ON═(C₁-C₆)alkyl-, orR²ON═CR²(C—C₆)alkyl-.

In a further preferred embodiment, R¹ of the compound of the method issubstituted by at least one of R²ON═.

In a further preferred embodiment, R¹ of the compound of the method issubstituted by at least one of —NR²(OR²).

In a further preferred embodiment, R¹ of the compound of the method issubstituted by at least one of R⁴R⁵NS(O)₂—, R⁴R⁵NS(O)₂(C₁-C₆)alkyl-,R⁴S(O)₂R⁵N—, or R⁴S(O)₂R⁵N(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ of the compound of the method issubstituted by at least one of R⁴S(O)₂R⁵N—.

In a further preferred embodiment, R¹ of the compound of the method issubstituted by at least one of R⁴S(O)₂R⁵N(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ of the compound of the method issubstituted by at least one of hydroxy(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ is a (C₃-C₈)cycloalkyl ring or(C₅-C₈)cycloalkenyl ring, wherein either the cycloalkyl ring orcycloalkenyl ring is substituted by one of R³C(O)O—,R³C(O)O—(C₁-C₆)alkyl-, R²ON═, R²ON═(C₁-C₆)alkyl-, R²ON═CR²(C₁-C₆)alkyl-,—NR²(OR²), R⁴R⁵NS(O)₂—, R⁴R⁵NS(O)₂(C₁-C₆)alkyl-, R⁴S(O)₂R⁵N—, orR⁴S(O)₂R⁵N(C₁-C₆)alkyl-; wherein R², R³, R⁴ and R⁵ are as defined above.

In a further preferred embodiment, R¹ is a (C₃-C₈)cycloalkyl ring or(C₅-C₈)cycloalkenyl ring, wherein either the cycloalkyl ring orcycloalkenyl ring is substituted by one of R³C(O)O—,R³C(O)O—(C₁-C₆)alkyl-, R²ON═, or R⁴S(O)₂R⁵N—; wherein R², R³, R⁴ and R⁵are as defined above.

In a preferred embodiment, R¹ is substituted by one of R³C(O)O— orR³C(O)O—(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ is substituted by one of R³C(O)O—.

In a further preferred embodiment, R₁ is substituted by one ofR³C(O)O—(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ is substituted by one of R²ON═,R²ON═(C₁-C₆)alkyl-, or R²ON═CR²(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ is substituted by one of R²ON═.

In a further preferred embodiment, R¹ is substituted by one of—NR²(OR²).

In a further preferred embodiment, R¹ is substituted by one ofR⁴R⁵NS(O)₂—, R⁴R⁵NS(O)₂(C₁-C₆)alkyl-, R⁴S(O)₂R⁵N—, orR⁴S(O)₂R⁵N(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ is substituted by one ofR⁴S(O)₂R⁵N—.

In a further preferred embodiment, R¹ is substituted by one ofR⁴S(O)₂R⁵N(C₁-C₆)alkyl-.

In a further preferred embodiment, R¹ of the compound of the method issubstituted by one of hydroxy(C₁-C₆)alkyl-.

The (C₂-C₉)heterocycloalkyl substituent, when present on R¹ of thecompound of formula 1, is preferably a group of the formula:

wherein m is as defined above, and

Z is CH₂, NR², O, S, SO, or SO₂.

For any of the aforementioned methods of the present invention, R¹ ofthe compound of formula I is preferably a group of the formula:

which is substituted as described above for R¹;

wherein n is 0, 1, or 2;

wherein the dashed line indicates an optional double bond at thatposition.

In a further preferred embodiment, n is 0 or 1.

In a further preferred embodiment, n is 0; and the dashed linerepresents a double bond at that position.

In a further preferred embodiment, n is 1.

In a further preferred embodiment, R¹ is substituted by ═O, ═NOH, CH₂OHor

or a combination thereof.

In a further preferred embodiment, n is 0; R¹ is substituted by ═NOH;and the dashed line represents a double bond at that position.

In further preferred embodiment, n is 1; and R¹ is substituted by ═O,═NOH, CH₂OH, or

or a combination thereof.

In a preferred embodiment, the method of the present invention comprisesadministering to a human a skin-lightening or pigmentation-reducingeffective amount of a compound selected from the group consisting of:

4-(2,4-Dihydroxyphenyl)cyclohexanone;

4-(2,4-Dihydroxyphenyl)cyclohexanone oxime;

O-Methyl-4-(2,4-dihydroxyphenyl)cyclohexanone oxime;

O-Benzyl-4-(2,4-dihydroxyphenyl)cyclohexanone oxime;

3-(2,4-dihydroxyphenyl)-2-cyclohexen-1-one;

(±)-3-(2,4-Dihydroxyphenyl)cyclohexanone;

3-(2,4-Dihydroxyphenyl)-2-cyclohexen-1-one oxime;

(±)-3-(2,4-Dihydroxyphenyl)cyclohexanone oxime;

(±)-4-[3-(1-Piperazinyl)cyclohexyl]-1,3-benzenediol;

(±)-N-[3-(2,4-Dihydroxyphenyl)cyclohexyl]methanesulfonamide;

(±)-4-[3-(Hydroxymethyl)cyclohexyl]-1,3-benzenediol;

(±)-4-[3-(Hydroxyamino)cyclohexyl]-1,3-benzenediol;

cis/trans-4-[4-(Hydroxymethyl)cyclohexyl]-1,3-benzenediol;

cis/trans-4-(4-Hydroxy-4-methylcyclohexyl)-1,3-benzenediol;

(±)-O-Methyl-3-(2,4-dihydroxyphenyl)cyclohexanone oxime;

(±)-3-(2,4-Dihydroxyphenyl)-1-methylcyclohexanol;

(±)-O-Benzyl-3-(2,4-dihydroxyphenyl)cyclohexanone oxime;

3-(2,4-Dihydroxyphenyl)-2-cyclopentenone oxime;

(±)-3-(2,4-Dihydroxyphenyl)cyclopentanone;

(±)-3-(2,4-Dihydroxyphenyl)cyclopentanone oxime;

and a pharmaceutically acceptable salt thereof.

In a further preferred embodiment, the method of the present inventioncomprises administering to a human a skin-lightening orpigmentation-reducing effective amount of a compound selected from thegroup consisting of:

4-(2,4-Dihydroxyphenyl)-3-cyclohexen-1-one;

cis/trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]acetamide;

cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-1-butanesulfonamide;

trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]methanesulfonamide;

cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]methanesulfonamide;

4-[4-(4-Hydroxyphenyl)cyclohexyl]-1,3-benzenediol;

cis/trans-Methyl [4-(2,4-dihydroxyphenyl)cyclohexyl]acetate;

trans-Methyl [4-(2,4-dihydroxyphenyl)cyclohexyl]acetate;

cis-Methyl [4-(2,4-dihydroxyphenyl)cyclohexyl]acetate;

trans-[4-(2,4-Dihydroxyphenyl)cyclohexyl]acetic acid;

cis-[4-(2,4-Dihydroxyphenyl)cyclohexyl]acetic acid;

cis/trans-[4-(2,4-Dihydroxyphenyl)cyclohexyl]acetic acid;

cis/trans-[4-(2,4-Dihydroxyphenyl)cyclohexyl]acetonitrile;

cis/trans-4-[4-(2-Aminoethyl)cyclohexyl]-1,3-benzenediol;

(±)-4-(3,3-Difluorocyclohexyl)-1,3-benzenediol;

(±)-3-(2,4-Dihydroxyphenyl)cyclohexanecarboxamide;

(±)-3-(2,4-Dihydroxyphenyl)-N-hydroxycyclohexanecarboxamide;

(±)-3-(2,4-Dihydroxyphenyl)-N-ethylcyclohexanecarboxamide;

(±)-4-[3-Hydroxy-3-(hydroxymethyl)cyclohexyl]-1,3-benzenediol;

(±)-N-[3-(2,4-dihydroxyphenyl)cyclohexyl]acetamide;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl) 4-(dimethylamino)benzoate;

cis/trans-4-(2,4-Dihydroxyphenyl)cyclohexanecarboxylic acid;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl ethylcarbamate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl cyclohexylcarbamate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-tert-butylbenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-fluorobenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-trifluoromethylbenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-methoxybenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-methylbenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-chlorobenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 3,4-dimethylbenzoate;

trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 3,4-dichlorobenzoate;

trans-4-[4-(Phenylsulfanyl)cyclohexyl]-1,3-benzenediol;

trans-4-[4-(Phenylsulfonyl)cyclohexyl]-1,3-benzenediol;

[4-(2,4-Dihydroxyphenyl)cyclohexyl]methyl propionate;

ethyl 4-(2,4-dihydroxyphenyl)-1-hydroxycyclohexane carboxylate;

cis/trans-4-[4-(hydroxyamino)cyclohexyl]-1,3-benzenediol;

trans-4-[4-(methoxyamino)cyclohexyl]-1,3-benzenediol;

and a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the method is carried out by administering askin-lightening or pigmentation-reducing effective amount of a compoundof the present invention to a human in need of said treatment.

In another preferred embodiment, the skin-lightening orpigmentation-reducing effective amount of a compound of the method ofthe present invention is a tyrosinase-inhibiting effective amount of thecompound.

The present invention further provides a method of inhibiting tyrosinasein a human, comprising administering to said human atyrosinase-inhibiting effective amount of a compound selected from amongthe compounds used in any of the aforementioned methods of the presentinvention. In a preferred embodiment, the method is carried out byadministering a tyrosinase-inhibiting effective amount of a compound ofthe present invention to a human in need of said treatment.

The present invention further provides a topical or transdermalpharmaceutical composition for the treatment of an inflammatory disordersuch as psoriasis, dermatitis or acne, or for the treatment of dandruff,in a human, comprising a pharmaceutically acceptable carrier, and anamount of a compound of formula I, or a pharmaceutically acceptable saltthereof, used in any of the aforementioned pharmaceutical compositionsof the present invention, which amount is effective in treating suchdisorder or condition.

The present invention further provides a method of treating inflammatorydisorders, such as psoriasis, dermatitis or acne, or a method oftreating dandruff, in a human, comprising administering to said human anamount of a compound of formula I or a pharmaceutically acceptable saltthereof, used in any of the aforementioned methods of the presentinvention, which amount is effective in treating such disorder orcondition.

The present invention further provides a use of any of the compoundsused in any of the aforementioned methods of the present invention, orany of the compounds used in any of the aforementioned pharmaceuticalcompositions of the present invention, to prepare a medicament useful inlightening skin or reducing pigmentation of skin in a human.

The term “alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, branched orcyclic moieties or combinations thereof. Any substituents or functionalgroups on the alkyl group, as indicated herein, can be substitutedanywhere on the alkyl group.

The term “aryl”, as used herein, refers to phenyl or naphthyl optionallysubstituted with one or more substituents, preferably from zero to twosubstituents, independently selected from halogen, OH, (C₁-C₆)alkyl,(C₁-C₆) alkoxy, amino, (C₁-C₆)alkylamino, di-((C₁-C₆)alkyl))amino,nitro, cyano and trifluoromethyl. Any substituents or functional groupson the aryl group, as indicated herein, can be substituted anywhere onthe aryl group.

The term “one or more substituents”, as used herein, refers to a numberof substituents that equals from one to the maximum number ofsubstituents possible based on the number of available bonding sites.

The “halo”, as used herein, refers to halogen and, unless otherwiseindicated, includes chloro, fluoro, bromo and iodo.

The term “acyl”, as used herein, unless otherwise indicated, includes aradical of the general formula RCO wherein R is alkyl, alkoxy, aryl,arylalkyl, or arylalkyloxy and the terms “alkyl” or “aryl” are asdefined above.

The term “acyloxy”, as used herein, includes O-acyl groups wherein“acyl” is as defined above.

(C₂-C₉)Heterocycloalkyl, when used herein, refers to pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl,thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl,isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,tetrahydroazepinyl, piperazinyl, chromanyl, etc. One of ordinary skillin the art will understand that the connection of said(C₂-C₉)heterocycloalkyl ring can be through a carbon atom or through anitrogen heteroatom where possible.

(C₂-C₉)Heteroaryl, when used herein, refers to furyl, thienyl,thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl,triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl,pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl,6,7-dihydro-5H-[1]pyridinyl, benzo[b]thiophenyl, 5, 6, 7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, benzoxazinyl, etc. One of ordinary skill inthe art will understand that the connection of said(C₂-C₉)heterocycloalkyl rings can be through a carbon atom or through anitrogen heteroatom where possible.

Compounds of formula I may contain chiral centers and therefore mayexist in different enantiomeric and diastereomeric forms. This inventionrelates to all optical isomers, stereoisomers and tautomers of thecompounds of formula I, and mixtures thereof, and to all pharmaceuticalcompositions and methods of treatment defined above that contain oremploy them, respectively.

Formula I, as defined above, also includes compounds identical to thosedepicted but for the fact that one or more hydrogen, carbon or otheratoms are replaced by isotopes thereof. Such compounds may be useful asresearch and diagnostic tools in metabolism pharmacokinetic studies andin binding assays.

The present invention also relates to the pharmaceutically acceptableacid addition and base salts of any of the aforementioned compounds offormula I. The acids which are used to prepare the pharmaceuticallyacceptable acid addition salts of the aforementioned base compounds ofthis invention are those which form non-toxic acid addition salts, i.e.,salts containing pharmacologically acceptable anions, such as thehydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,phosphate, acid phosphate, acetate, lactate, citrate, acid citrate,tartrate, bitartrate, succinate, maleate, fumarate, gluconate,saccharate, benzoate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

As used herein, a “skin-lightening or pigmentation reducing amount of acompound of formula I”, and the like, means an amount or concentrationof the compound capable of detectably lightening skin or reducingpigmentation in a human, as determined by any standard assay. The activecompound is typically administered in a pharmaceutical composition andfor a standard course of treatment that produces the desired result ofskin depigmentation.

As used herein, a “tyrosinase-inhibiting effective amount of a compoundof formula I”, and the like, means an amount or concentration of thecompound capable of detectably inhibiting tyrosinase activity in ahuman, as determined by any standard assay, such as those describedbelow.

As used herein, an “amount of a compound of formula I capable oftreating an inflammatory disorder such as psoriasis, dermatitis or acne,or treating dandruff”, and the like, means an amount or concentration ofthe compound capable of detectably ameliorating, reducing, eliminating,slowing, or preventing the progression of, any symptom or conditionassociated with or caused by such disorder or condition, in a human, asdetermined by any standard assay.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula I may be prepared as described in the followingreaction schemes and discussion. Unless otherwise indicated, n, m, R²,R³, R⁴, R⁵, Z, and structural formula I in the reaction schemes anddiscussion that follow are as defined above.

Y, Y^(I), Y^(II) shown in the schemes above each independentlyrepresents any of the various substituents on R¹ as defined above, orhydrogen as appropriate.

Reaction Schemes 1 through 12 illustrate various methods of synthesizingcompounds of formula I. PG refers to a protecting group.

Referring to Scheme 1, compounds of formula (2) can be formed byprotecting commercially available 4-bromoresorcinol (1). A suitableprotecting group such as methoxymethyl (MOM) can be introduced byconventional methods that are well known to those skilled in the art.For example, alkylation of 4-bromoresorcinol can occur with twoequivalents of methoxymethyl chloride in the presence ofdiisopropylamine in a halogenated solvent at about 0° C. to roomtemperature.

Compounds of general formula (3) can be obtained using conventionalmethods. For example, the reaction of compounds of formula (2) withn-butyllithium in the presence of N,N,N′,N′-tetramethylethylenediaminein a suitable solvent such as tetrahydrofuran, followed by quenchingwith triisopropyl borate and hydrolysing with aqueous acid, can yieldcompounds of formula (3).

Compounds of general formula (5) can be obtained using conventionalmethods. For example, the treatment of compounds of formula (4) withtriphenylphosphine and bromine in a chlorinated solvent will yieldcompounds of formula (5). Compound (4) where n=1 is commerciallyavailable (Aldrich, Milwaukee, Wis., USA).

Compounds of formula (6) can be obtained by reacting compounds offormula (3) with compounds of formula (5) under Suzuki couplingconditions. For example, the Suzuki reaction can be carried out usingpalladium tetrakis (triphenylphosphine)palladium (five mole percent),sodium carbonate (two equivalents) and heating in a suitable solventsystem (e.g., dimethoxyethane/water) at about 80° C. Conversion ofcompounds of formula (6) to compounds of formula (8) can occur understandard reducing conditions, such as, e.g., hydrogen gas and a metalcatalyst such as rhodium on alumina, at about room temperature andatmospheric pressure. Deprotection of compounds of formula (6) or (8)under suitable conditions, e.g., where the protecting group is MOM,heating at 50° C. in methanol with acidic Dowex, gives compounds offormula I where R¹ is substituted with ═O (7), (9). Compounds of formula(7) or (9) can be further derivatised under standard conditions to yieldresorcinols of formula I where R¹ is substituted with ═NOR 2. Forexample, heating compounds of formula (7) in a suitable solvent (e.g.,ethanol) at about 80° C. with the required hydroxylamine hydrochloridesalt and triethylamine yields the analogues of formula I. Compounds offormula I where R¹ is substituted with NHOR² can be prepared fromcompounds of formula I where R¹ is substituted with ═NOR² by a reductionunder standard reaction conditions, e.g., sodium cyanoborohydride inacetic acid at or about room temperature.

Compounds of formula (8) can be further derivatised under standardconditions to yield resorcinols of formula I where R¹ is disubstitutedwith fluoro. For example, treating compounds of formula (8) withdiethylaminosulfur trifluoride in a suitable solvent, e.g.dimethoxyethane, after suitable deprotection, would give analogues offormula I.

Referring to Scheme 2, compounds of the general formula (10) are wellknown and can be obtained using conventional methods (see, e.g., Crombieet al., 1982, J. Chem. Soc. Perkin Trans. I, 1485). Compounds of formula(11) can be obtained from the reaction of compounds of formula (2) withn-butyllithium in the presence of N,N,N′,N′-tetramethylethylenediaminein an ethereal solvent, followed by the addition of a compound offormula (10). Dehydration of compounds of formula (11) under standardconditions, e.g., heating compounds of formula (11) at about 110° C. ina Dean-Stark apparatus in the presence of camphor sulfonic acid in asuitable solvent (e.g., toluene), yields compounds of formula (12).Hydrogenation under standard conditions, e.g., using hydrogen gas andpalladium on charcoal in ethanol, yields compounds of the generalformula (13). Deprotection under suitable conditions yields resorcinolsof formula I where R¹ is substituted with ═O (14). Compounds of formula(14) can be further derivatised under standard conditions to yieldresorcinols of formula I where R¹ is substituted with ═NOR². Forexample, heating compounds of formula (14) in a suitable solvent (e.g.,ethanol) at about 80° C. with the required hydroxylamine hydrochloridesalt and triethylamine yields analogues of formula 1. Further reductionunder standard conditions would yield compounds of formula 1, where R¹is substituted with NHOR². Compounds of formula (14) can also bereprotected with a suitable protecting group such astert-butyldimethylsilyl under standard reaction conditions to yieldcompounds of formula (15).

Compounds of formula (15) can be further derivatised using standardreaction conditions. For example, methylenation using an appropriateWittig will yield compounds of formula (16), e.g., treatment ofmethyltriphenylphosphonium bromide with potassium t-butoxide in asuitable solvent (e.g., tetrahydrofuran) at a temperature between −78°C. and 0° C., followed by the addition of a compound of formula (15)will yield compounds of formula (16). Subsequent conversion to compoundsof formula (18) under standard conditions, e.g. hydroboration, to givecompounds of formula (17), and further oxidation using suitableconditions, such as pyridinium dichromate in dimethylformamide at roomtemperature, gives compounds of formula (18). Compounds of formula (17)can be treated with an alkyl bromide in a suitable solvent (e.g.,acetone) in the presence of potassium carbonate to yield compounds offormula I where R¹ is substituted with an ether group after suitabledeprotection has taken place, e.g. when the protecting group istert-butyldimethylsilyl, tetrabutylammonium fluoride in tetrahydrofurancan be used. Alternatively, compounds of formula (17) can also beesterified under standard conditions, e.g. treatment with an acidchloride in the presence of triethylamine in a chlorinated solvent atabout room temperature. Compounds of formula (18) can be derivatised toform analogues such as esters and amides under conditions well known tothose with skill in the art. For example, conditions to form amides mayinvolve treating compounds of formula (18) with iso-butylchloroformateand triethylamine in a chlorinated solvent at about 0° C., followed bythe addition of a suitable amine. Deprotection under suitable conditionswill yield compounds of formula I where R¹ is substituted with an amide.Deprotection of compounds of formula (16), (17) and (18) under standardconditions also provides compounds of formula I where R¹ is substitutedwith methylene, hydroxylmethyl or a carboxylic acid, respectively.

Referring to Scheme 3, compounds of formula (20) can be preparedstarting with compound (19), which is commercially available. Conversionto compounds of formula (20) can occur under standard conditions suchas, for example, where the protecting group is benzyl, condensation canoccur between compound (19) and benzyl alcohol with the removal of waterusing a Dean-Stark apparatus in conjunction with well known methodology.Condensation of compounds of formula (20) with compounds of formula (10)can occur using standard techniques, for example, treatment of compoundsof formula (20) with a base such as lithium diisopropylamide in anethereal solvent followed by the addition of a compound of formula (10)would give compounds of formula (21). Treatment of compounds of formula(21) with a suitable reagent such as N-bromosuccinimide in a chlorinatedsolvent at about room temperature can give compounds of formula (22).Compounds of formula (23) can then be generated from compounds offormula (22) under suitable conditions. Such conditions can involvetreating compounds of formula (22) with a base such as1,8-diazobicyclo[5.4.0]undec-7-ene in a suitable solvent such asN,N-dimethylformamide at about 140° C. Treatment of compounds of formula(23) to standard hydrogenation conditions, e.g., hydrogen gas andpalladium on charcoal in ethanol, yields compounds of the generalformula (24) when the protecting group is benzyl. Compounds of formula(14) can then be obtained by treating compounds of formula (24) toacidic conditions.

Conversion of compounds of formula (14) to compounds of formula I mayinvolve the need to use protecting groups that will be obvious to thoseof skill in the art. Some examples of such compounds of formula I areillustrated in Scheme 3. Conversion of compounds of formula (15) tocompounds of formula I may involve the reduction of the ketone moietyunder standard conditions, e.g., sodium borohydride in ethanol. Furtherderivitisation can occur, e.g. using chemistry described elsewhere inthis document, to give compounds of formula I where Y¹ may be alkyl,acyl or a carbonylamino. In examples where protecting groups have beenused, suitable deprotection will be required to yield compounds offormula I.

Alternatively, compounds of formula (15) can be manipulated to givecompounds of formula I where R¹ is substituted with an amide orsulfonamide. Treatment of compounds of formula (15) with benzylamineunder reductive amination conditions, e.g., one equivalent of sodiumtriacetoxyborohydride in a suitable solvent (dichloroethane) followed byhydrogenolysis under standard conditions, e.g., palladium on charcoal,hydrogen gas, ethanol, provides compounds of formula (25). Synthesis ofcompounds of formula I can be obtained using conventional methods. Forexample, compounds of formula (25) can react with sulfonyl chlorides andacid chlorides in a chlorinated solvent in the presence of a base (e.g.triethylamine) at about room temperature. Deprotection using suitablereaction conditions provides compounds of formula I where Y is asulfonamide or amide group.

Referring to Scheme 4, compounds of formula (26) can be synthesizedusing standard methods. For example, compounds of formula (6) or (8) canbe homologated using a Wittig reaction and further manipulated asdescribed above to yield compounds of formula 1. Compounds of formula(26) or (16) from Scheme 2 can also undergo dihydroxylation understandard conditions, e.g. catalytic osmium tetroxide and N-methylmorpholine in an ethereal solvent, and after suitable deprotection yieldcompounds of formula I where R¹ is substituted with —(OH)(CH₂OH).

Referring to Scheme 5, compounds of formula (29) can be obtained byreacting compounds (6) or (8) as described above in Scheme 3. Compoundsof formulae (29) and (25) can also be derivatised by treating with analkylating agent, e.g., an alkyl iodide in a chlorinated solvent in thepresence of triethylamine at about room temperature, to give compound(30) prior to sulfonylation or amide bond formation and deprotection, toyield compounds of formula I wherein Y is —N(R⁵)SO₂R⁴ or equivalentamide where R⁵ is not hydrogen.

Referring to Scheme 6, compounds of formula (6), (8) or (9), (14) or(15) can be treated with a suitable organometallic reagent, such as aGrignard reagent, in an ethereal solvent at a temperature between −78°C. and 0° C., followed by deprotection to yield compounds of formula Iwhere R¹ is substituted with (R²)OR².

Referring to Scheme 7, compounds of formula (31) can be formed underconditions well known to those skilled in the art. Treatment ofcompounds (6) or (8) with an amine, such as piperidine, in a suitablesolvent (e.g., dichloroethane) and a reducing agent such as sodiumtriacetoxyborohydride, followed by deprotection will yield compounds offormula I where R¹ is substituted with a nitrogen-containingheterocycle.

Referring to Scheme 8, compounds of general formula (33) can be obtainedusing conventional methods. For example, the reaction of compounds offormula (2) with n-butyllithium in the presence ofN,N,N′,N′-tetramethylethylenediamine in a suitable solvent such astetrahydrofuran, followed by quenching with ketone (32) (commerciallyavailable from Aldrich), and hydrolysing with aqueous acid, can yieldcompounds of formula (33). Functional group manipulation as outlined inSchemes 1-7 and Scheme 8 then allows the synthesis of compounds offormula 1.

Referring to scheme 9, compounds of formula (15), (6) or (8) can befurther derivatised to yield compounds of formula (34) using standardWittig or Wadworths-Emmons chemistry, followed by suitable deprotection.Compounds of formula (34) can be reduced using standard hydrogenation asdescribed above to yield compounds where Y is OH, O-alkyl, or anaminoalkyl. Standard Wadworths-Emmons chemistry can also yield compoundsof formula (35). Reduction under suitable conditions will yieldcompounds of formula (36), which can be further derivatised usingstandard chemistry described previously in this document to givecompounds where NY^(I)Y^(II) is an amide, sulfonamide, or aminoalkyl.

Referring to Scheme 10, compounds of formula (10) can be converted intocompounds of formula (37) using standard alkylation procedures. Forexample, compound (10) can be treated with a suitable base such aslithium diisopropyl amide in a suitable solvent such as tetrahydrofuranat a temperature between −78° C. and 0° C., followed by the addition ofa suitable alkylating agent. Such alkylating agents are well known tothose of skill in the art, and can include chloro, bromo, or iodoalkylcompounds; epoxides; aldehydes; aziridines; α,β-unsaturated esters,ketones or amides; acyl chlorides; electrophilic sources of oxygen suchas Mo(CO)₅pyridine (Crimmons, M. T. et al., 1992, J. Am. Chem. Soc.,114:5445); or electrophilic sources of nitrogen such as2,4,6-triisopropylbenzene sulfonyl azide (Evans, P. A. et al., 1992,Tetrahedron Lett. 33:6959). Such alkylating reagents are commerciallyavailable or can be prepared by standard procedures well known to thoseof skill in the art.

Compounds of formula (37) can be further manipulated using methodologysimilar to that described above. For instance, alkylation of compoundsof formula (37) under conditions of kinetic deprotonation (see, e.g.,Kopka, I. and Rathke, M. W., 1981, J. Org. Chem. 46:3771), followed byalkylation as previously described, would yield compounds of formula(38). Alternatively, alkylation of compounds of formula (37) underconditions of thermodynamic deprotonation (Kopka and Rathke, 1981,above), followed by alkylation as previously described, would yieldcompounds of formula (45). Further alkylation or functional groupmanipulation known to those of skill in the art and, as describedelsewhere in this document, followed by removal of the carbonylprotecting group under standard conditions, e.g., aqueous hydrochloricacid at about 0° C. to 50° C., would yield compounds of formulae (40),(46), and (49).

Compounds of formula (37) can also be protected with a suitableprotecting group, e.g., ethylenedithio ketal, and after removal of theketal protecting group under standard reaction conditions, e.g., aqueoushydrochloric acid at about 0° C. to 50° C., would allow furtherfunctionalisation of the cycloalkyl ring using the methodology describedabove to yield compounds of formula (44).

Referring to Scheme 11, compounds of formula (50) can be formed fromcompounds of formula (10) using known methodology (see, e.g., Adam, W.et al., 1989, Tetrahedron Lett. 30:6497) (Ts=tosyl). Standard functionalgroup manipulation yields compounds of formula (55) and (57). Oxiranering cleavage by an amine yields compounds of formula (51).Alternatively, acid hydrolysis yields compounds of formula (52).Conversion of the corresponding alcohol to a leaving group such aspara-toluenesulfonyl would allow the nucleophilic displacement with arange of nucleophiles under standard, well-known conditions. Suchnucleophiles may include amines, thiolates, alkoxides, and carbon-basednucleophiles such as cyanide, which are commercially available orprepared by standard procedures well known to those of skill in the art.

Compounds of formula (40), (44) and (49) can be prepared using theabove-described methods or other methods known in the art such thatsubstituents on R¹ are as defined above.

Referring to Schemes 10 and 11, ketones of formulae (37), (38), (40),(42), (43), (44), (45), (46), (47), (49), (51), (54), (55), and (57) canbe further manipulated as described in Schemes 1-9 above, and convertedinto compounds of formula I as described in Schemes 2 and 3.

Referring to Scheme 12, compounds of formula I can also be preparedusing the methodology described above. Compounds of formula (58) can beconverted into compounds of formula I using the chemistry as describedin Schemes 1-11 above.

It will be appreciated by those of skill in the art that in theprocesses described above, the functional groups of intermediatecompounds may need to be protected by protecting groups. The use ofprotecting groups is well-known in the art, and is fully described,among other places, in: Protecting Groups in Organic Chemistry, J. W. F.McOmie, (ed.), 1973, Plenum Press; and in: Protecting Groups in OrganicSynthesis, 2^(nd) edition, T. W. Greene & P. G. M. Wutz, 1991,Wiley-Interscience, which are incorporated by reference in theirentirety.

The compounds of the present invention can also synthesized byapplication of alternative synthetic routes, such as those described inEuropean Patent Application No. EP 1134207 A1 by Pfizer Products Inc,published Sep. 19, 2001.

The compounds of formula I that are basic in nature are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate a compound of formula I from the reaction mixture as apharmaceutically unacceptable salt and then simply convert the latterback to the free base compound by treatment with an alkaline reagent andsubsequently convert the latter free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the activebase compounds of this invention are readily prepared by treating thebase compound with a substantially equivalent amount of the chosenmineral or organic acid in an aqueous solvent medium or in a suitableorganic solvent, such as methanol or ethanol. Upon careful evaporationof the solvent, the desired solid salt is readily obtained.

Those compounds of formula I that are acidic in nature are capable offorming base salts with various pharmaceutically acceptable cations.Examples of such salts include the alkali metal and alkaline earth metalsalts and, particularly, the sodium and potassium salts. These salts canbe prepared by conventional techniques. The chemical bases that are usedas reagents to prepare the pharmaceutically acceptable base salts ofthis invention are those that form non-toxic base salts with the acidiccompounds of formula I. Such non-toxic base salts include those derivedfrom such pharmaceutically acceptable cations as sodium, potassium,calcium and magnesium, etc. These salts can easily be prepared bytreating the corresponding acidic compounds with an aqueous solutioncontaining the desired pharmaceutically acceptable cations, and thenevaporating the resulting solution to dryness, preferably under reducedpressure. Alternatively, they can also be prepared by mixing loweralkanolic solutions of the acidic compounds and the desired alkali metalalkoxide together, and then evaporating the resulting solution todryness, as described above. In either case, stoichiometric quantitiesof reagents are preferably employed in order to ensure completeness ofreaction and maximum yields of the desired final products.

Compounds of formula I and their pharmaceutically acceptable salts(hereinafter “the active compounds used in this invention”) are usefulin the treatment of disorders of human pigmentation, including solar andsimple lentigines (including age/liver spots), melasma/chloasma andpostinflammatory hyperpigmentation. Such compounds reduce skin melaninlevels by inhibiting the production of melanin, whether the latter isproduced constitutively or in response to UV irradiation (such as sunexposure). Thus, the active compounds used in this invention can be usedto reduce skin melanin content in non-pathological states so as toinduce a lighter skin tone, as desired by the user, or to preventmelanin accumulation in skin that has been exposed to UV irradiation.They can also be used in combination with skin peeling agents (includingglycolic acid or trichloroacetic acid face peels) to lighten skin toneand prevent repigmentation. The appropriate dose regimen, the amount ofeach dose administered, and specific intervals between doses of theactive compound will depend upon the particular active compoundemployed, the condition of the patient being treated, and the nature andseverity of the disorder or condition being treated. Preferably, theactive compound is administered in an amount and at an interval thatresults in the desired treatment of or improvement in the disorder orcondition being treated.

An active compound used in the present invention can also be used incombination with sun screens (UVA or UVB blockers) to preventrepigmentation, to protect against sun or UV-induced skin darkening orto enhance their ability to reduce skin melanin and their skin bleachingaction. An active compound used in the present invention can also beused in combination with retinoic acid or its derivatives or anycompounds that interact with retinoic acid receptors and accelerate orenhance the invention's ability to reduce skin melanin and skinbleaching action, or enhance the invention's ability to prevent theaccumulation of skin melanin. An active compound used in the presentinvention can also be used in combination with 4-hydroxyanisole.

The active compounds used in this invention can also be used incombination with ascorbic acid, its derivatives and ascorbic-acid basedproducts (such as magnesium ascorbate) or other products with ananti-oxidant mechanism (such as resveratrol) which accelerate or enhancetheir ability to reduce skin melanin and their skin bleaching action.

Occurrences in the skin or hair of noticeable but undesired pigmentationas a result of melanin production, overproduction or underproduction canbe treated using the methods of the present invention. Cosmeticapplications for methods of the present invention include the topicalapplication of compositions containing one or more of the compounds ofthe present invention to enhance or otherwise alter the visualappearance of skin or hair. The cosmetic compositions of the presentinvention are also useful to provide a smoother or softer skinappearance or texture.

As one skilled in the art would know in view of this disclosure, anactive compound used in the methods of the present invention may be usedalone or in combination with other compounds known in the art to affectmelanin synthesis, particularly other melanin synthesis inhibitors,including tyrosinase inhibitors. Such inhibitors include those currentlyknown in the art and those to be developed in the future. Knowninhibitors include various resorcinol derivatives, kojic acidderivatives, hydroquinone, melamine, and various types of plantextracts, among others. For example, any of the compounds used accordingto a skin-lightening method of the present invention may be used incombination with a tyrosinase inhibitor or other skin-whitening agent,including any one or more of those agents, including compounds orextracts, described in the following patent publications: U.S. Pat. No.4,278,656 to Nagai et al, issued Jul. 14, 1981, describing the use ofkojic acid and its derivatives; U.S. Pat. No. 4,369,174 to Nagai et al.,issued Jan. 18, 1983, describing the use of kojic acid and itsderivatives; U.S. Pat. No. 4,959,393 to Torihara et al., issued Sep. 25,1990, describing the use of 4-n-butylresorcinol, 4-isoamyl resorcinoland other resorcinol derivatives; U.S. Pat. No. 5,580,549 to Fukuda etal., issued Dec. 3, 1996, describing the use of various hydroxybenzoicacid derivatives; U.S. Pat. No. 6,123,959 to Jones et al., issued Sep.26, 2000, describing the use of liposomes containing combinations ofcompetitive inhibitors, such as arbutin, and non-competitive inhibitors,such as aloesin, of melanin synthesis; U.S. Pat. No. 6,132,740 to Hu,issued Oct. 17, 2000, describing the use of various resorcinolderivatives; U.S. Pat. No. 6,159,482 to Tuloup et a al., issued Dec. 12,2000, describing the use of various hydroxyphenyl oxamate derivatives;WO 99/32077 by L'Oreal, published Jul. 1, 1999, describing the use ofvarious phenolic amides; WO 99/64025 by Fytokem Prod. Inc., publishedDec. 16, 1999, describing the use of various dicotyledonous plantextracts; WO 00/56702 by Pfizer Inc., published Sep. 28, 2000 describingvarious resorcinol derivatives; WO 00/76473 by Shiseido Co. Ltd.,published Dec. 12, 2000, describing the use of Withania plant extracts;EP 997140 by L'Oreal SA, published May 3, 2000, describing the use ofcombinations of mulberry and skullcap extracts with salicylic acidderivatives; JP 5221846 by Kunimasa Tomoji, published Aug. 31, 1993,describing the use of kojic acid derivatives; JP 7242687 by Shiseido Co.Ltd., published Sep. 19, 1995, describing the use of Trichodermaextracts; JP 7324023 by Itogawa H, published Dec. 12, 1995, describingthe use of Pseudostellariae radix extracts; JP 8012552 by Shiseido Co.Ltd., published Jan. 16, 1996, describing the use of Amor seco extracts;JP 8012554 by Shiseido Co. Ltd., published Jan. 16, 1996, describing theuse of Jabonciilo extracts; JP 8012557 by Shiseido Co. Ltd., publishedJan. 16, 1996, describing the use of Huaca extracts; JP 8012560 byShiseido Co. Ltd., published Jan. 16, 1996, describing the use ofCopaiba extracts; JP 8012561 by Shiseido Co. Ltd., published Jan. 16,1996, describing the use of Arnica extracts; JP 8134090 by Fujisawa,published May 28, 1996, describing the use of galactosyl-kojic acidderivatives; JP 8168378 by Kirinjo KK, published Jul. 2, 1996,describing the use of lees from rice wine production; JP 8277225 byKansai Koso KK, published Oct. 22, 1996, describing the use ofAutocarpus incisus extracts; JP 9002967 by Sanki Shoji KK, publishedJan. 7, 1997, describing the use of Prunus domesticus extracts; JP9295927 by Yagi Akira, published Nov. 18, 1997, describing the use ofAloe vera extracts; JP 10072330 by Kansai Kouso, published Mar. 17,1998, describing the use of oxydesberatrol derivatives; JP 10081626 byKamiyama KK, published Mar. 31, 1998, describing the use of4-substituted benzoic acids; JP 10101543 by Kansai Kouso KK, publishedApr. 21, 1998, describing the use of flavonoids; JP 11071231 by MaruzenPharm., published Mar. 16, 1999, describing the use of bakuchiol; JP11079934 by Kyodo Nyugyo, published Mar. 23, 1999, describing the use oflow molecular weight thiol from sake lees; JP 11246347 by Shiseido Co.Ltd., published Sep. 14, 1999, describing the use of Achilleamillefolium extracts; JP 11246344 by Shiseido Co. Ltd., published Sep.14, 1999, describing the use of Gliricidia extracts; JP 2000-080023 byKanebo Ltd., published Mar. 21, 2000, describing the use ofmetallothionine inducers; JP 2000-095663 by Kose KK, published Apr. 4,2000, describing the use of various plant extracts; JP 2000-159681 byHai Tai Confectionary Co. Ltd., published Jun. 13, 2000, describing theuse of grape seed extract; JP-7206753 by Nikken Food KK, published Aug.8, 1995, describing the use of dihydroxycurcumin derivatives; JP-5320025by Kunimasa T, published Dec. 3, 1993, describing the use of kojic acidderivatives; and JP-59157009 by Yakurigaku Chuou K E, published Sep. 6,1984, describing the use of P-thujaplicin, hydroquinone or a pyronecompound in combination with a melanin adsorbent; among others; whichpatent publications are incorporated herein by reference in theirentireties.

This invention relates both to methods of lightening or reducing thepigmentation of skin in which the compound of formula I, orpharmaceutically acceptable salt thereof, and one or more of the otheractive ingredients referred to above are administered together, as partof the same pharmaceutical composition, as well as methods in which theyare administered separately as part of an appropriate dose regimendesigned to obtain the benefits of the combination therapy. Theappropriate dose regimen, the amount of each dose administered, andspecific intervals between doses of each active agent will depend uponthe specific combination of active agents employed, the condition of thepatient being treated, and the nature and severity of the disorder orcondition being treated. Such additional active ingredients willgenerally be administered in amounts less than or equal to those forwhich they are effective as single topical therapeutic agents. The FDAapproved dosages for such active agents that have received FDA approvalfor administration to humans are publicly available.

The active compounds of the present invention are generally administeredin the form of pharmaceutical compositions comprising at least one ofthe compounds of formula (I), together with a pharmaceuticallyacceptable vehicle or diluent. Alternatively, an active compound of thisinvention can be administered in the form of a cosmetic compositioncomprising at least one compound of formula (I), together with acosmetically acceptable vehicle or diluent. Such compositions aregenerally formulated in a conventional manner utilizing solid or liquidvehicles or diluents as appropriate for topical administration, in theform of solutions, gels, creams, jellies, pastes, lotions, ointments,salves, aerosols and the like.

Examples of vehicles for application of the active compounds of thisinvention include an aqueous or water-alcohol solution, an emulsion ofthe oil-in-water or water-in-oil type, an emulsified gel, or a two-phasesystem. Preferably, the compositions according to the invention are inthe form of lotions, creams, milks, gels, masks, microspheres ornanospheres, or vesicular dispersions. In the case of vesiculardispersions, the lipids of which the vesicles are made can be of theionic or nonionic type, or a mixture thereof. Such vehicles can includesuitable viscosity enhancing agents, pH adjusting agents, stabilizers,fragrances, etc., as known in the art of topical formulations.

An effective dosage and treatment protocol can be determined byconventional means, starting with a low dose in laboratory animals andthen increasing the dosage while monitoring the effects, andsystematically varying the dosage regimen as well. Animal studies,preferably mammalian studies, are commonly used to determine the maximaltolerable dose, or MTD, of a bioactive agent per kilogram weight. Thoseskilled in the art can a extrapolate doses for efficacy and avoidance oftoxicity to other species, including humans.

Before human studies of efficacy are undertaken, Phase I clinicalstudies in normal subjects can help establish safe doses. Numerousfactors can be taken into consideration by a clinician when determiningan optimal dosage for a given subject. Primary among these is thetoxicity and half-life of the chosen compound. Additional factorsinclude the size of the patient, the age of the patient, the generalcondition of the patient, the particular disease, condition, or disorderbeing treated, the severity of the disease, condition, or disorder beingtreated, the presence of other drugs in the patient, the effect desired,and the like. The trial dosages would be chosen after consideration ofthe results of animal studies and the clinical literature.

One of ordinary skill in the art will appreciate that the endpoint oftreatment chosen in a particular case will vary according to thedisease, condition, or disorder being treated, the outcome desired bythe patient, subject, or treating physician, and other factors. Wherethe composition is being used to lighten skin color such as, forexample, to reverse hyperpigmentation caused by, for example,inflammation or diseases such as melasma, or to lighten hair color, anyone of a number of endpoints can be chosen. For example, endpoints canbe defined subjectively such as, for example, when the subject is simply“satisfied” with the results of the treatment. For pharmacologicalcompositions, the endpoint can be determined by the patient's, or thetreating physician's, satisfaction with the results of the treatment.Alternatively, endpoints can be defined objectively. For example, thepatient's or subject's skin or hair in the treated area can be comparedto a color chart. Treatment is terminated when the color of the skin orhair in the treated area is similar in appearance to a color on thechart. Alternatively, the reflectance of the treated skin or hair can bemeasured, and treatment can be terminated when the treated skin or hairattains a specified reflectance. Alternatively, the melanin content ofthe treated hair or skin can be measured. Treatment can be terminatedwhen the melanin content of the treated hair or skin reaches a specifiedvalue. Melanin content can be determined in any way known to the art,including by histological methods, with or without enhancement by stainsfor melanin.

In the depigmenting compositions according to the present invention, theconcentration of the active compound of the invention is generallybetween 0.01 and 10%, preferably between 0.1 and 10%, relative to thetotal weight of the composition.

The compositions of this invention can optionally also contain amoistener, a surfactant, keratolytic, an anti-inflammatory agent, acomplexing agent, an antioxidant, a preservative, a colorant, afragrance, or a sunscreen.

The compositions of the present invention can be applied directly to theskin. Alternatively, they can be delivered by various transdermal drugdelivery systems, such as transdermal patches as known in the art. Forexample, for topical administration, the active ingredient can beformulated in a solution, gel, lotion, ointment, cream, suspension,paste, liniment, powder, tincture, aerosol, patch, or the like in apharmaceutically or cosmetically acceptable form by methods well knownin the art. The composition can be any of a variety of forms common inthe pharmaceutical or cosmetic arts for topical application to animalsor humans, including solutions, lotions, sprays, creams, ointments,salves, gels, etc., as described below. Preferred agents are those thatare viscous enough to remain on the treated area, those that do notreadily evaporate, and/or those that are easily removed by rinsing withwater, optionally with the aid of soaps, cleansers and/or shampoos.Actual methods for preparing topical formulations are known or apparentto those skilled in the art, and are described in detail in Remington'sPharmaceutical Sciences, 1990 (supra); and Pharmaceutical Dosage Formsand Drug Delivery Systems, 6th ed., Williams & Wilkins (1995).

In order to enhance the percutaneous absorption of the activeingredients, one or more of a number of agents can be added in thetopical formulations including, but not limited to, dimethylsulfoxide,dimethylacetamide, dimethylformamide, surfactants, azone, alcohol,acetone, propylene glycol and polyethylene glycol. In addition, physicalmethods can also be used to enhance transdermal penetration such as,e.g., by iontophoresis or sonophoresis. Alternatively, or in addition,liposomes may be employed.

A topically applied composition of the invention contains apharmaceutically effective agent that lightens skin as described herein,and those ingredients as are necessary for use as a carrier, such as anemulsion, a cream, an ointment, an aqueous solution, a lotion or anaerosol. Non-limiting examples of such carriers are described in moredetail below and may be found in International Patent Publication WO00/62742, published Oct. 26, 2000; U.S. Pat. No. 5,691,380 to Mason etal., issued Nov. 25, 1997; U.S. Pat. No. 5, 968,528 to Deckner et al.,issued Oct. 19, 1999; U.S. Pat. No. 4,139,619 to Chidsey, III, issuedFeb. 13, 1979; and U.S. Pat. No. 4,684,635 to Orentreich et al., issuedAug. 4, 1987; which are incorporated herein by reference. Suitablepharmaceutical carriers are further described in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.(1990), which is a standard reference text in this field.

The pharmaceutical compositions of the invention may optionally includecomponents suitable for application to keratinous tissue, that is, whenincorporated into the composition, they are suitable for use in contactwith human keratinous tissue without undue toxicity, incompatibility,instability, allergic response, and the like within the scope of soundmedical judgment. In addition, such optional components are usefulprovided that they do not unacceptably alter the benefits of the activecompounds of the invention. The CTFA Cosmetic Ingredient Handbook,Second Edition (1992) describes a wide variety of non-limiting cosmeticand pharmaceutical ingredients commonly used in the skin care industry,which are suitable for use in the compositions of the present invention.Examples of these ingredient classes include: abrasives, absorbents,aesthetic components such as fragrances, pigments, colorings/colorants,essential oils, skin sensates, astringents, etc. (e.g., clove oil,menthol, camphor, eucalyptus oil, eugenol, menthyl lactate, witch hazeldistillate), anti-acne agents, anti-caking agents, antifoaming agents,antimicrobial agents (e.g., iodopropyl butylcarbamate), antioxidants,binders, biological additives, buffering agents, bulking agents,chelating agents, chemical additives, colorants, cosmetic astringents,cosmetic biocides, denaturants, drug astringents, external analgesics,film formers or materials, e.g., polymers, for aiding the film-formingproperties and substantivity of the composition (e.g., copolymer ofeicosene and vinyl pyrrolidone), opacifying agents, pH adjusters,propellants, reducing agents, sequestrants, skin-conditioning agents(e.g., humectants, including miscellaneous and occlusive), skin soothingand/or healing agents (e.g., panthenol and derivatives (e.g., ethylpanthenol), aloe vera, pantothenic acid and its derivatives, allantoinand bisabolol and dipotassium glycyrrhizinate), skin treating agents,thickeners, and vitamins and derivatives thereof.

In addition to the pharmaceutically effective amount of an agentdisclosed herein, the topical compositions of the present invention alsocomprise a dermatologically acceptable carrier. The phrase“dermatologically acceptable carrier”, as used herein, means that thecarrier is suitable for topical application to the skin, i.e.,keratinous tissue, has good aesthetic properties, is compatible with theactive agents of the present invention and any other components, andwill not cause any safety or toxicity concerns. A safe and effectiveamount of carrier is from about 50% to about 99.99%, preferably fromabout 80% to about 99.9%, more preferably from about 90% to about 98%,and most preferably from about 90% to about 95% of the composition.

The carrier utilized in the compositions of the invention can be in awide variety of forms. These include emulsion carriers, including, butnot limited to, oil-in-water, water-in-oil, water-in-oil-in-water, andoil-in-water-in-silicone emulsions, a cream, an ointment, an aqueoussolution, a lotion or an aerosol. As will be understood by the skilledartisan, a given component will distribute primarily into either thewater or oil/silicone phase, depending on the watersolubility/dispersibility of the component in the composition.

Emulsions according to the present invention generally contain apharmaceutically effective amount of an agent disclosed herein and alipid or oil. Lipids and oils may be derived from animals, plants, orpetroleum and may be natural or synthetic (i.e., man-made). Preferredemulsions also contain a humectant, such as glycerin. Emulsions willpreferably further contain from about 1% to about 10%, more preferablyfrom about 2% to about 5%, of an emulsifier, based on the weight of thecarrier. Emulsifiers may be nonionic, anionic or cationic. Suitableemulsifiers are described in, for example, U.S. Pat. No. 3,755,560 toDickert et al., issued Aug. 28, 1973; U.S. Pat. No. 4,421,769 to Dixon,et al., issued Dec. 20, 1983; and McCutcheon's Detergents andEmulsifiers, North American Edition, pages 317-324 (1986).

The emulsion may also contain an anti-foaming agent to minimize foamingupon application to the keratinous tissue. Anti-foaming agents includehigh molecular weight silicones and other materials well known in theart for such use.

Suitable emulsions may have a wide range of viscosities, depending onthe desired product form. Exemplary low viscosity emulsions, which arepreferred, have a viscosity of about 50 centistokes or less, morepreferably about 10 centistokes or less, most preferably about 5centistokes or less. The emulsion may also contain an anti-foaming agentto minimize foaming upon application to the keratinous tissue.Anti-foaming agents include high molecular weight silicones and othermaterials well known in the art for such use.

One type of emulsion is a water-in-silicone emulsion. Water-in-siliconeemulsions contain a continuous silicone phase and a dispersed aqueousphase. Preferred water-in-silicone emulsions of the present inventioncomprise from about 1% to about 60%, preferably from about 5% to about40%, more preferably from about 10% to about 20%, by weight of acontinuous silicone phase. The continuous silicone phase exists as anexternal phase that contains or surrounds the discontinuous aqueousphase described hereinafter.

The continuous silicone phase may contain a polyorganosiloxane oil. Apreferred water-in-silicone emulsion system is formulated to provide anoxidatively stable vehicle for delivery of a pharmaceutically effectiveamount of an agent disclosed herein. The continuous silicone phase ofthese preferred emulsions comprises between about 50% and about 99.9% byweight of organopolysiloxane oil and less than about 50% by weight of anon-silicone oil. In an especially preferred embodiment, the continuoussilicone phase comprises at least about 50%, preferably from about 60%to about 99.9%, more preferably from about 70% to about 99.9%, and evenmore preferably from about 80% to about 99.9%, polyorganosiloxane oil byweight of the continuous silicone phase, and up to about 50%non-silicone oils, preferably less than about 40%, more preferably lessthan about 30%, even more preferably less than about 10%, and mostpreferably less than about 2%, by weight of the continuous siliconephase. These useful emulsion systems may provide more oxidativestability over extended periods of time than comparable water-in-oilemulsions containing lower concentrations of the polyorganosiloxane oil.Concentrations of non-silicone oils in the continuous silicone phase areminimized or avoided altogether so as to possibly further enhanceoxidative stability of the active compound of the invention in thecompositions. Water-in-silicone emulsions of this type are described inU.S. Pat. No. 5,691,380 to Mason et al., issued Nov. 25, 1997.

The organopolysiloxane oil for use in the composition may be volatile,non-volatile, or a mixture of volatile and non-volatile silicones. Theterm “nonvolatile” as used in this context refers to those siliconesthat are liquid under ambient conditions and have a flash point (underone atmospheric of pressure) of or greater than about 100 degreesCelsius. The term “volatile” as used in this context refers to all othersilicone oils. Suitable organopolysiloxanes can be selected from a widevariety of silicones spanning a broad range of volatilities andviscosities. Examples of suitable organopolysiloxane oils includepolyalkylsiloxanes, cyclic polyalkylsiloxanes, andpolyalkylarylsiloxanes, which are known to those skilled in the art andcommercially available.

The continuous silicone phase may contain one or more non-silicone oils.Concentrations of non-silicone oils in the continuous silicone phase arepreferably minimized or avoided altogether so as to further enhanceoxidative stability of the pharmaceutically effective agent in thecompositions. Suitable non-silicone oils have a melting point of about25° C. or less under about one atmosphere of pressure. Examples ofnon-silicone oils suitable for use in the continuous silicone phase arethose well known in the chemical arts in topical personal care productsin the form of water-in-oil emulsions, e.g. mineral oil, vegetable oils,synthetic oils, semisynthetic oils, etc.

Useful topical compositions of the present invention comprise from about30% to about 90%, more preferably from about 50% to about 85%, and mostpreferably from about 70% to about 80% of a dispersed aqueous phase. Inemulsion technology, the term “dispersed phase” is a term well-known toone skilled in the art which means that the phase exists as smallparticles or droplets that are suspended in and surrounded by acontinuous phase. The dispersed phase is also known as the internal ordiscontinuous phase. The dispersed aqueous phase is a dispersion ofsmall aqueous particles or droplets suspended in and surrounded by thecontinuous silicone phase described hereinbefore. The aqueous phase canbe water, or a combination of water and one or more water soluble ordispersible ingredients. Non-limiting examples of such optionalingredients include thickeners, acids, bases, salts, chelants, gums,water-soluble or dispersible alcohols and polyols, buffers,preservatives, sunscreening agents, colorings, and the like.

The topical compositions of the present invention typically comprisefrom about 25% to about 90%, preferably from about 40% to about 80%,more preferably from about 60% to about 80%, water in the dispersedaqueous phase by weight of the composition.

The water-in-silicone emulsions of the present invention preferablycomprise an emulsifier. In a preferred embodiment, the compositioncontains from about 0.1% to about 10% emulsifier, more preferably fromabout 0.5% to about 7.5%, most preferably from about 1% to about 5%,emulsifier by weight of the composition. The emulsifier helps disperseand suspend the aqueous phase within the continuous silicone phase.

A wide variety of emulsifying agents can be employed herein to form thepreferred water-in-silicone emulsion. Known or conventional emulsifyingagents can be used in the composition, provided that the selectedemulsifying agent is chemically and physically compatible with essentialcomponents of the composition, and provides the desired dispersioncharacteristics. Suitable emulsifiers include silicone emulsifiers,e.g., organically modified organopolysiloxanes, also known to thoseskilled in the art as silicone surfactants, non-silicon-containingemulsifiers, and mixtures thereof, known by those skilled in the art foruse in topical personal care products.

Useful emulsifiers include a wide variety of silicone emulsifiers. Thesesilicone emulsifiers are typically organically modifiedorganopolysiloxanes, also known to those skilled in the art as siliconesurfactants. Suitable emulsifiers are described, for example, inMcCutcheon's, Detergents and Emulsifiers, North American Edition (1986),published by Allured Publishing Corporation; U.S. Pat. No. 5,011,681 toCiotti et al., issued Apr. 30, 1991; U.S. Pat. No. 4,421,769 to Dixon etal., issued Dec. 20, 1983; and U.S. Pat. No. 3,755,560 to Dickert etal., issued Aug. 28, 1973.

Other preferred topical carriers include oil-in-water emulsions, havinga continuous aqueous phase and a hydrophobic, water-insoluble phase(“oil phase”) dispersed therein. Examples of suitable carrierscomprising oil-in-water emulsions are described in U.S. Pat. No.5,073,371 to Turner et al., issued Dec. 17, 1991; and U.S. Pat. No.5,073,372, to Turner et al., issued Dec. 17, 1991. An especiallypreferred oil-in-water emulsion, containing a structuring agent,hydrophilic surfactant and water, is described in detail hereinafter.

A preferred oil-in-water emulsion comprises a structuring agent toassist in the formation of a liquid crystalline gel network structure.Without being limited by theory, it is believed that the structuringagent assists in providing Theological characteristics to thecomposition which contribute to the stability of the composition. Thestructuring agent may also function as an emulsifier or surfactant.Preferred compositions of this invention comprise from about 0.5% toabout 20%, more preferably from about 1% to about 10%, most preferablyfrom about 1% to about 5%, by weight of the composition, of astructuring agent. The preferred structuring agents of the presentinvention are selected from the group consisting of stearic acid,palmitic acid, stearyl alcohol, cetyl alcohol, behenyl alcohol, stearicacid, palmitic acid, the polyethylene glycol ether of stearyl alcoholhaving an average of about 1 to about 21 ethylene oxide units, thepolyethylene glycol ether of cetyl alcohol having an average of about 1to about 5 ethylene oxide units, and mixtures thereof.

The preferred oil-in-water emulsions comprise from about 0.05% to about10%, preferably from about 1% to about 6%, and more preferably fromabout 1% to about 3% of at least one hydrophilic surfactant which candisperse the hydrophobic materials in the water phase (percentages byweight of the topical carrier). The surfactant, at a minimum, must behydrophilic enough to disperse in water. Suitable surfactants includeany of a wide variety of known cationic, anionic, zwitterionic, andamphoteric surfactants. See McCutcheon's. Detergents and Emulsifiers(1986), supra; U.S. Pat. No. 5,011,681 to Ciotti et al., issued Apr. 30,1991; U.S. Pat. No. 4,421,769 to Dixon et al. issued Dec. 20, 1983; andU.S. Pat. No. 3,755,560 to Dickert et al., issued Aug. 28, 1973. Theexact surfactant chosen depends upon the pH of the composition and theother components present. Preferred are cationic surfactants, especiallydialkyl quaternary ammonium compounds, examples of which are describedin U.S. Pat. No. 5,151,209 to McCall et al. issued Sep. 29, 1992; U.S.Pat. No. 5,151,210 to Steuri et al. issued Sep. 29, 1992; U.S. Pat. No.5,120,532 to Wells et al, issued Jun. 9, 1992; U.S. Pat. No. 4,387,090to Bolich Jr., issued Jun. 7, 1983; U.S. Pat. No. 3,155,591 to Hilfer,issued Nov. 3, 1964; U.S. Pat. No. 3,929,678 to Laughlin et al, issuedDec. 30, 1975; U.S. Pat. No. 3,959,461 to Bailey et al., May 25, 1976;McCutcheon's, Detergents & Emulsifiers (North American edition 1979)M.C. Publishing Co.; and Schwartz, et al., Surface Active Agents, TheirChemistry and Technology, New York: Interscience Publishers, 1949.

Alternatively, other useful cationic emulsifiers include amino-amides.Non-limiting examples of these cationic emulsifiers includestearamidopropyl PG-dimonium chloride phosphate, behenamidopropyl PGdimonium chloride, stearamidopropyl ethyldimonium ethosulfate,stearamidopropyl dimethyl (myristyl acetate) ammonium chloride,stearamidopropyl dimethyl cetearyl ammonium tosylate, stearamidopropyldimethyl ammonium chloride, stearamidopropyl dimethyl ammonium lactate,and mixtures thereof.

A wide variety of anionic surfactants are also useful herein. See, e.g.,U.S. Pat. No. 3,929,678, to Laughlin et al., issued Dec. 30, 1975. Inaddition, amphoteric and zwitterionic surfactants are also usefulherein.

The preferred oil-in-water emulsion comprises from about 25% to about98%, preferably from about 65% to about 95%, more preferably from about70% to about 90% water by weight of the topical carrier.

The hydrophobic phase is dispersed in the continuous aqueous phase. Thehydrophobic phase may contain water-insoluble or partially solublematerials such as are known in the art, including but not limited to thesilicones described herein in reference to silicone-in-water emulsions,and other oils and lipids such as described above in reference toemulsions.

The topical compositions of the subject invention, including but notlimited to lotions and creams, may comprise a dermatologicallyacceptable emollient. Such compositions preferably contain from about 2%to about 50% of the emollient. As used herein, “emollient” refers to amaterial useful for the prevention or relief of dryness, as well as forthe protection of the skin. A wide variety of suitable emollients areknown and may be used herein. See, e.g., Sagarin, Cosmetics, Science andTechnology, 2nd Edition, Vol. 1, pp. 3243 (1972), which containsnumerous examples of materials suitable as an emollient. A preferredemollient is glycerin. Glycerin is preferably used in an amount of fromor about 0.001 to or about 20%, more preferably from or about 0.01 to orabout 10%, most preferably from or about 0.1 to or about 5%, e.g., 3%.

Lotions and creams according to the present invention generally comprisea solution carrier system and one or more emollients. Lotions typicallycomprise from about 1% to about 20%, preferably from about 5% to about10% of emollient; from about 50% to about 90%, preferably from about 60%to about 80% water; and a pharmaceutically effective amount of an agentdescribed herein. A cream typically comprises from about 5% to about50%, preferably from about 10% to about 20% of emollient; from about 45%to about 85%, preferably from about 50% to about 75% water; and apharmaceutically effective amount of an agent described herein.

Ointments of the present invention may comprise a simple carrier base ofanimal or vegetable oils or semi-solid hydrocarbons (oleaginous);absorption ointment bases, which absorb water to form emulsions; orwater soluble carriers, e.g., a water soluble solution carrier.Ointments may further comprise a thickening agent, such as described inSagarin, Cosmetics, Science and Technology, 2nd Edition, Vol. 1, pp.72-73 (1972), incorporated herein by reference, and/or an emollient. Forexample, an ointment may comprise from about 2% to about 10% of anemollient; from about 0.1% to about 2% of a thickening agent; and apharmaceutically effective amount of an agent described herein.

By way of non-limiting example, 1000 g of topical cream is prepared fromthe following types and amounts of ingredients: a pharmaceuticallyeffective amount of an agent disclosed herein, tegacid regular (150 g)(a self-emulsifying glyceryl monostearate from Goldschmidt ChemicalCorporation, New York, N.Y.), polysorbate 80 (50 g), spermaceti (100 g),propylene glycol (50 g), methylparaben (1 g), and deionized water insufficient quantity to reach 1000 gm. The tegacid and spermaceti aremelted together at a temperature of 70-80° C. The methylparaben isdissolved in about 500 g. of water and the propylene glycol, polysorbate80, and active compound are added in turn, maintaining a temperature of75-800 C. The methylparaben mixture is added slowly to the tegacid andspermaceti melt, with constant stirring. The addition is continued forat least 30 minutes with additional stirring until the temperature hasdropped to 40-45° C. Finally, sufficient water is added to bring thefinal weight to 1000 g. and the preparation stirred to maintainhomogeneity until cooled and congealed.

By way of non-limiting example, 1000 g of a topical ointment is preparedfrom the following types and amounts of ingredients: a pharmaceuticallyeffective amount of an agent disclosed herein, zinc oxide (50 g),calamine (50 g), liquid petrolatum (heavy) (250 g), wool fat (200 g),and enough white petrolatum to reach 1000 g. Briefly, the whitepetrolatum and wool fat are melted and 100 g of liquid petrolatum addedthereto. The pharmaceutically effective amount of an agent disclosedherein, zinc oxide, and calamine are added to the remaining liquidpetrolatum and the mixture milled until the powders are finely dividedand uniformly dispersed. The mixture is stirred into the whitepetrolatum, melted and cooled with stirring until the ointment congeals.

By way of non-limiting example, 1000 g of an ointment containing apharmaceutically effective amount of an agent disclosed herein isprepared from the following types and amounts of ingredients: apharmaceutically effective amount of an agent disclosed herein, lightliquid petrolatum (250 g), wool fat (200 g), and enough white petrolatumto reach 1000 g. Briefly, the pharmaceutically effective amount of anagent disclosed herein is finely divided and added to the light liquidpetrolatum. The wool fat and white petrolatum are melted together,strained, and the temperature adjusted to 45-50° C. The liquidpetrolatum slurry is added, and the ointment stirred until congealed.

By way of non-limiting example, 1000 ml of an aqueous solutioncontaining a pharmaceutically effective amount of an agent disclosedherein is prepared from the following types and amounts of ingredients:a pharmaceutically effective amount of an agent disclosed herein,polyethylene glycol 4000 (120 g) myristyl-gamma-picolinium chloride (0.2g), polyvinylpyrrolidone (1 g), and enough deionized water to reach 1000milliliters. Briefly, the ingredients are dissolved in the water and theresulting solution is sterilized by filtration.

By way of non-limiting example, 1000 g of lotion containing apharmaceutically effective amount of an agent disclosed herein isprepared from the following types and amounts of ingredients: apharmaceutically effective amount of an agent disclosed herein, N-methylpyrolidone (40 g), and enough propylene glycol to reach 1000 g.

By way of non-limiting example, an aerosol containing a pharmaceuticallyeffective amount of an agent disclosed herein is prepared from thefollowing types and amounts of materials: a pharmaceutically effectiveamount of an agent disclosed herein, absolute alcohol (4.37 g),dichlorodifluoroethane (1.43 g) and dichlorotetrafluoroethane (5.70 g).Briefly, the pharmaceutically effective amount of an agent disclosedherein is dissolved in the absolute alcohol and the resulting solutionfiltered to remove particles and lint. This solution is chilled to aboutminus 30° C. Then, to this is added the chilled mixture ofdichlorodifluoromethane and dichlorotetrafluoroethane.

For oral administration, gelatin capsules or liquid-filled soft gelatincapsules can contain the active ingredient and powdered or liquidcarriers, such as lactose, lecithin starch, cellulose derivatives,magnesium stearate, stearic acid, and the like. Similar diluents can beused to make compressed tablets. Both tablets and capsules can bemanufactured as sustained release products to provide for continuousrelease of medication over a period of hours. Compressed tablets can besugar-coated or film-coated to mask any unpleasant taste and to protectthe tablet from the atmosphere, or enteric-coated for selective,targeted disintegration in the gastrointestinal tract. Liquid dosageforms for oral administration can contain coloring and/or flavoring toincrease patient acceptance.

In general, sterile water, oil, saline, aqueous dextrose (glucose),polysorbate and related sugar solutions and glycols such as propyleneglycol or polyethylene glycols, are suitable carriers for parenteralsolutions. Solutions or emulsions for parenteral administrationpreferably contain about 5-15% polysorbate 80 or lecithin, suitablestabilizing agents and, if necessary, buffer substances. Anti-oxidizingagents such as, but not limited to, sodium bisulfite, sodium sulfite, orascorbic acid, either alone or combined, are suitable stabilizingagents. Also useful are citric acid and its salts, and sodium EDTA. Inaddition, parenteral solutions can contain preservatives including, butnot limited to, benzalkonium chloride, methyl- or propyl-paraben, andchlorobutanol.

Additional examples of particular formulations comprising an activecompound of the present invention are provided below.

An example of the preparation of a topical gel follows.

TABLE 1 Topical Gel: Ingredient Percent by Weight Active compound 0.50Propylene glycol 20.00 Ethanol 20.00 Carboxyvinyl polymer [Carbomer940 ™] 1.00 Hydroxyethyl cellulose 0.40 Benzyl alcohol 1.00 Sodiumhydroxide 1N to pH 6 Distilled water Balance

The components other than sodium hydroxide are combined to yield ahomogeneous dispersion. Addition of sodium hydroxide causes the mixtureto gel yielding a ready-to-use semisolid.

An example of the preparation of a topical cream follows.

TABLE 2 Topical Cream: Ingredient Percent by Weight Active compound 0.50Stearic acid 7.00 Stearyl alcohol 5.00 Cetyl alcohol 2.00 Glycerin 10.00Sodium laurylsulfate 1.00 Propylparaben 0.05 Methylparaben 0.25 Disodiumedetate 0.05 Distilled water Balance

The first four ingredients are heated to approximately 70° C. to producea uniform melt. The remaining ingredients are combined, heated toapproximately 75° C., and added with mixing to the previously preparedmelt. The emulsion thus formed is subsequently homogenized and cooled toyield a smooth white cream.

An example of the preparation of a topical lotion follows.

TABLE 3 Topical Lotion: Ingredient Percent by Weight Active compound0.50 Glyceryl monostearate 1.00 Isopropyl palmitate 4.00 Polyethyleneglycol 400 distearate 2.00 Glycerin 10.00 Methylparaben 0.10 Sodiumcetylsulfate 5.00 Distilled water Balance

The first four ingredients are combined and heated to approximately 70°C., then added with agitation to a mixture of the remaining ingredients,also at about 70° C. The emulsion is appropriately homogenized andcooled to produce a smooth, white, pourable lotion.

An example of the preparation of a topical solution follows.

TABLE 4 Topical Solution: Ingredient Percent by Weight Active compound0.50 Propylene glycol 20.00 Ethanol 50.00 Benzyl alcohol 1.00 Disodiumedetate 0.01 Propyl gallate 0.10 Citric acid 0.20 Sodium hydroxide 1N topH 6 Distilled water Balance

All ingredients except sodium hydroxide are combined with agitation, andthe pH of the resultant solution is adjusted with 1 N sodium hydroxide,to pH 6, to yield a free-flowing, quick-drying topical solution.

The topical formulations presented herein are examples of typical gel,cream, lotion, or solution dosage forms of active compounds for use inlightening skin. Other optional components can be added or excipientratios can be adjusted to enhance cosmetic acceptability of theformulations. Additionally, these alterations can be made to customizethe composition toward a particular active compound, for example, toensure solubilization or to enhance chemical or physical stability.Optional components would include viscosity adjusters such ascelluloses, emollient oils such as mineral oil or glycerides, humectantssuch as polyols, cosolvents such as isopropyl alcohol or acetone,emulsifying agents of the anionic, cationic and non-ionic types,preservatives, antioxidants, opacifiers, colorants and perfumes.

An example of the preparation of an oral tablet formulation follows.

TABLE 5 Tablet Formulation: Ingredient Amount (mg) Active Compound 25Lactose 50 Cornstarch (for mix) 10 Cornstarch (paste) 10 Magnesiumstearate (1%)  5 Total 100 

The active compound, lactose, and cornstarch (for mix) are blended touniformity. The cornstarch (for paste) is suspended in 200 mL of waterand heated with stirring to form a paste. The paste is used to granulatethe mixed powders. The wet granules are passed through a No. 8 handscreen and dried at 80° C. The dry granules are lubricated with the 1%magnesium stearate and pressed into a tablet.

An example of the preparation of an oral solution follows.

TABLE 6 Oral Solution: Ingredient Percent by Weight Active Compound 2.0Ethyl alcohol 10.0 Benzyl alcohol 1.0 Peppermint flavor 0.2 Vanillin 0.2Polysorbate 40 0.1 Sucrose 50.0 Purified water Balance

The ingredients are combined and mixed to form a uniform solution.

The present invention further provides a kit comprising a containercomprising a pharmaceutical composition of the present invention. Thecontainer is designed to prevent contamination, minimize evaporation ordrying of the composition, etc. The composition may or may not beprovided in a preset unit dose or usage amount. The kit may furthercomprise a package insert comprising printed instructions directing theuse of the pharmaceutical composition for lightening the skin.

The ability of compounds of formula I to inhibit tyrosinase may bedetermined using any of the following procedures.

1. Tyrosinase (DOPA oxidase) Assay Using Cell Lysate:

Human melanoma cell line, SKMEL 188 (licensed from MemorialSloan-Kettering), is used in the cell lysate assay and the screen. Inthe assay, compounds and L-dihydroxyphenylalanine (L-DOPA) (100 μg/ml)are incubated with the cell lysates containing human tyrosinase for 8hrs before the plates are read at 405 nm. Potency of the compounds inDOPA oxidase assay is correlated very well with that in tyrosinehydroxylase assay using ³H-tyrosine as a substrate. Most of thecompounds of formula I that were tested in this assay exhibited an IC₅₀of less than 10 μM. For example, the compound of Example 23, i.e.,(±)-3-(2,4-Dihydroxyphenyl)cyclopentanone oxime, had an IC₅₀ in thisassay of about 2 μm.

2. Melanin Assay in Human Primary Melanocytes:

Compounds are incubated with human primary melanocytes in the presenceof α-melanocyte stimulating hormone (α-MSH) for 2-3 days. Cells are thenlysed with sodium hydroxide and sodium dodecyl sulfate (SDS) and melaninsignals are read at 405 nm. Alternatively, ¹⁴C-DOPA is added to thecells in combination with tyrosinase inhibitors and acid-insoluble¹⁴C-melanin is quantitated by a scintillation counter. IC₅₀'s reflectthe inhibitory potency of the compounds in the new melanin synthesisthat was stimulated by α-MSH.

3. Tyrosine Kinase Assay (TK):

TK assays can be performed using purified tyrosine kinase domains ofc-met, erb-B2, or IGF-r. A specific antibody against phosphorylatedtyrosine residue is used in the assay. Colorimetric signals aregenerated by horse radish peroxidase, which is conjugated to theantibody.

4. Human Skin Equivalent Model:

A mixture of human melanocytes and keratinocytes is grown in anair-liquid interphase. This tissue culture forms a three dimensionalstructure that histologically and microscopically resembles the humanskin epidermis. Test compounds are added on top of the cells to mimictopical drug application. After incubation with the compounds (10 μM)for 3 days, the cells are washed extensively and lysed for DOPA oxidaseassay.

5. IL-1 Assay (Interleukin-1 Assay):

An IL-1α ELISA assay (R&D system) can be used to evaluate the effect ofcompounds on IL-1 secretion in a human skin equivalent model. IL-1α is apro-inflammatory cytokine and plays a role in UV-induced skininflammation.

6. In vivo Study:

Black or dark brown guinea pigs with homogeneous skin color can be usedin this study. A solution of the test compound of formula I (5% inethanol:propylene glycol, 70:30) and the vehicle control are applied tothe animals twice daily, 5 days per week for 4-8 weeks. Using thisassay, depigmentation can be determined by subtracting the lightreflectance of untreated skin from the light reflectance of treatedskin.

The present invention is illustrated by the following examples. It willbe understood, however, that the invention is not limited to thespecific details of these examples. Melting points are uncorrected.Proton nuclear magnetic resonance spectra (400 MHz ¹H NMR) were measuredfor solutions in d₆-DMSO, CDCl₃, or d₄-MeOH, and peak positions areexpressed in parts per million (ppm) downfield from tetramethylsilane(TMS). The peak shapes are denoted as follows: s, singlet; d, doublet;t, triplet; q, quartet, m, multiplet, b, broad.

The following examples are illustrative only, and are not intended tolimit the scope of the present invention.

EXAMPLES Intermediate 1 1-Bromo-2,4-bis(methoxymethoxy)benzene

An oven dried 250 ml round bottomed flask equipped with magneticstirrer, under an argon atmosphere, was loaded with 4-bromoresorcinol(9.45 g, 50 mmol) and CH₂Cl₂ (50 ml). The stirred suspension was cooledto 0° C. and diisopropylamine (19.1 ml, 110 mmol) was added in oneportion via syringe. Stirring of the red solution was continued for afurther ten minutes before methyl chloromethyl ether (10.7 ml, 120 mmol)was added dropwise, via syringe, ensuring the internal temperature didnot exceed 10° C. The resulting yellow solution was then allowed to warmto room temperature overnight. Ammonium hydroxide solution (50 mL, 50%)was poured into the reaction vessel and stirring was continued for onehr. The mixture was poured into a separating funnel and the phasesseparated. The aqueous phase was then extracted with CH₂Cl₂ (3×30 ml)and the combined organics washed with brine (20 ml), dried overanhydrous magnesium sulphate, filtered and concentrated in vacuoaffording an orange oil. Purification was achieved by flash columnchromatography, (SiO₂, ethyl acetate/petroleum ether, 1:1, v/v),furnishing the title product (10.7 g, 77%) as a pale yellow oil.δ_(H)(CDCl₃) 7.42 (1H, d), 6.88 (1H, d), 6.64 (1H, dd), 5.24 (2H, s),5.15 (2H, s), 3.53 (3H, s), 3.48 (3H, s).

Intermediate 2

8-[2,4-Bis(methoxymethoxy)phenyl]-1,4-dioxaspiror[4.5]decan-8-ol

A round bottomed flask, equipped with magnetic stirrer, under an argonatmosphere was loaded with 1-bromo-2,4-bis(methoxymethoxy)benzene (2.00g, 7.2 mmol) and THF (50 mL). N,N,N′,N′-Tetramethylethylene diamine (2.3ml, 15.2 mmol) was added in one portion via syringe and the stirredsolution was cooled to −78° C. n-Butyl lithium (9.5 ml, 15.2 mmol, 1.6Min hexane) was added dropwise via syringe. The resulting yellow solutionwas stirred for 1 hr at −78° C. and 1,4-cyclohexanedione monoethyleneketal (1.35 g, 8.7 mmol) was added as a solution in THF (25 ml) slowly,via syringe. The resulting solution was stirred at −78° C. for 1 hr andthen allowed to warm to room temperature overnight. Hydrochloric acid(20 ml, 2M) was added and the reaction mixture stirred vigorously for 15min. Ethyl acetate (100 ml) was added and the mixture poured into aseparating funnel. The phases were separated and the aqueous phase wasextracted with ethyl acetate (3×20 ml). The combined organics werewashed with brine (20 ml), dried over anhydrous magnesium sulphate,filtered and concentrated affording an orange oil which was purified byflash column chromatography (SiO₂, ethyl acetate/petroleum ether, 45:55,v/v). The title product (1.42 g, 56%) was isolated as a colourless oil.m/z (ES⁺) 337 (M−H₂O+H⁺); δ_(H)(CDCl₃) 1.61-1.64(2H, m), 2.00-2.18(6H,m), 3.44(3H, s), 3.48(3H, s), 3.90-3.97(4H, m), 5.11(2H, s), 5.24(2H,s), 6.64(1H, dd), 6.82(1H, d), 7.20(1H, d).

Intermediate 38-[2,4-Bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]dec-7-ene

8-[2,4-Bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]decan-8-ol (1.40 g,3.95 mmol) was placed in a 50 ml round bottomed flask equipped withmagnetic stirrer and Dean-Stark apparatus. Toluene (30 ml) was added,followed by camphor sulphonic acid (10 mg). The stirred solution wasthen heated under reflux for 1 hr, cooled and saturated aqueous sodiumbicarbonate solution (10 ml) added. The mixture was poured into aseparating funnel and the phases separated. The aqueous phase wasextracted with ethyl acetate (2×15 ml) and the combined organics werewashed with brine (15 ml), dried over anhydrous magnesium sulphate,filtered and then concentrated in vacuo yielding an orange oil which waspurified by flash column chromatography (SiO₂, ethyl acetate/petroleumether, 45:55, v/v) to afford the title product (0.94 g) as a colourlessoil. δ_(H)(CDCl₃) 1.84 (2H, t), 2.41-2.43 (2H, m), 2.56-2.62 (2H, m),3.47 (6H, s), 3.98-4.02 (4H, m), 5.13 (4H, s), 5.58-5.63 (1H, m), 6.64(1H, dd), 6.78 (1H, d), 7.08 (1H, d).

Intermediate 48-[2,4-Bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]decane

8-[2,4-Bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]dec-7-ene (0.950 g,2.83 mmol) and palladium (200 mg, 10% on carbon) were stirred under anatmosphere of hydrogen for 15 hr. The mixture was then filtered througha plug of Celite, washing with ethyl acetate. The filtrate was thenevaporated to dryness, affording the desired product (0.955 g, 100%) asa colourless oil. δ_(H)(CDCl₃) 1.67-1.87 (8H, m), 2.90-2.99 (1H, m),3.46 (3H, s), 3.48 (3H, s), 3.97 (4H, s), 5.12 (2H, s), 5.18 (2H, s),6.65 (1H, dd), 6.78 (1H, d), 7.12 (1H, d).

Intermediate 5 4-[2,4-Bis(methoxymethoxy)phenyl]cyclohexanone

A round bottomed flask equipped with magnetic stirrer was charged with8-[2, 4-bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]decane (3.20 g9.47 mmol) and methanol (50 ml). Over a 20 min period, aqueoushydrochloric acid (50 ml, 1.00M) was added to the stirred solution, atroom temperature and the reaction mixture stirred for 1.5 hr. Solidsodium bicarbonate was added until the reaction mixture was neutralisedand the solvent was removed under reduced pressure. The residue waspartitioned between ethyl acetate (30 ml) and water (10 ml), and theaqueous layer was extracted with ethyl acetate (3×20 ml). The combinedorganic layers were washed with brine (10 ml), dried over magnesiumsulfate, filtered and concentrated in vacuo. The crude product waspurified via flash column chromatography (SiO₂, ethyl acetate/petroleumether, 1:4, v/v), affording the title compound (2.20 g, 60%) as a whitepowder. δ_(H)(CDCl₃) 1.85-1.96 (2H, m), 2.14-2.22 (2H, m), 2.46-2.59(4H, m), 3.39 (1H, tt), 3.49 (3H, s), 3.52 (3H, s), 5.16 (2H, s), 5.23(2H, s), 6.67-6.71 (1H, m), 6.85 (1H, m), 7.08 (1H, d).

Intermediate 6 3-[2,4-bis(methoxymethoxy) phenyl]-2-cyclohexen-1-one

Aqueous sodium carbonate (2 ml of a 6M solution) and2,4-bis(methoxymethoxy)phenylboronic acid (120 mg) in ethanol (2 ml)were added to a solution of palladium tetrakis(triphenylphosphine) (57mg) and 3-bromo-2-cyclohexen-1-one (87 mg) in dimethoxyethane (3 ml) andthe mixture was heated under reflux. After 6 hr, the mixture waspartitioned between water (50 ml) and ethyl acetate (100 ml). Theorganic layer was dried over magnesium sulfate and evaporated in vacuoto furnish an oil that was purified by flash column chromatography(SiO₂, ethyl acetate/petroleum ether, 1:3, v/v) to furnish the titlecompound as an oil (120 mg, 83%). δ_(H)(CDCl₃) 2.10 (2H, quintet), 2.47(2H, t), 2.74 (2H, m), 3.476 (3H, s), 3.484 (3H, s), 5.185 (2H, s),5.190 (2H, s), 6.21 (1H, m), 6.71 (1H, dd), 6.85 (1H, d), 7.16 (1H, d).

Intermediate 7 (±)-3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexanone

A suspension of 3-[2,4-bis(methoxymethoxy)phenyl]-2-cyclohexen-1-one(300 m g) and palladium catalyst (50 mg, 10% palladium on carbon) inethanol was stirred at ambient temperature under 1 atmosphere ofhydrogen. After 16 hr, the mixture was filtered through celite and thefiltrate was evaporated in vacuo. The product was dissolved indichloromethane (15 ml). Celite and pyridinium chlorochromate (430 mg)were added and the mixture was stirred at room temperature. After 3 hr,the mixture was filtered through a pad of silica and eluted withpetroleum ether/ethyl acetate (10:3, v/v), then purified by flash columnchromatography (SiO₂, petroleum ether/ethyl acetate 4:1 v/v) to furnishthe title compound as an oil (200 mg, 70%). δ_(H)(CDCl₃) 1.7-1.9 (2H,overlapping m), 2.05 (1H, m), 2.15 (1H, m), 2.35-2.60 (4H, overlappingm), 3.37 (1H, m), 3.490 (3H, s), 3.492 (3H, s), 5.15 (2H, s), 5.20 (2H,s), 6.70 (1H, dd), 6.82 (1H, d), 7.09 (1H, d).

Intermediate 8 3-(2,4-Dimethoxymethoxyphenyl)-2-cyclohexen-1-one Oxime

3-[2,4-Bis(methoxymethoxy)phenyl]-2-cyclohexen-1-one (200 mg),hydroxylamine hydrochloride (72 mg) and triethylamine (0.14 ml) wereheated under reflux in ethanol (10 ml). After 3 hr, the cooled reactionmixture was partitioned between water and ethyl acetate. The organiclayer was dried over magnesium sulfate and evaporated in vacuo tofurnish the title compound as an oil (206 mg, 99%). m/z (ES⁺) 308(M+H)⁺.

Intermediate 9(±)-1-{3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexyl}piperazine

(±)-3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexanone (80 mg) andpiperazine (24 mg) were dissolved in dichloroethane (5 ml) and stirredat ambient temperature for 1 hr under argon. Tetramethylammoniumtriacetoxyborohydride (79 mg) was added and stirring continued underargon. After 16 hr, additional portions of piperazine (24 mg) andtetramethylammonium triacetoxyborohydride (79 mg) were added andstirring continued. After a further 6 hr, glacial acetic acid was addeddropwise until a solution was obtained, and stirring continued atambient temperature. After a further 16 hr, the reaction mixture waspartitioned between sodium hydrogen carbonate (20 ml of a saturatedsolution) and ethyl acetate. The aqueous layer was extracted with ethylacetate (3×20 ml), and the combined organic extracts were dried overmagnesium sulfate and evaporated in vacuo. The crude residue waspurified by flash column chromatography chromatography (SiO₂,dichloromethane/methanol, 9:1 v/v) to furnish the title compound as anoff white solid (52 mg, 53%) and mixture of diastereoisomers; m/z (ES⁺)365 (M+H)⁺.

Intermediate 10 (±)-3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexylamine

Nickel chloride hexahydrate (77 mg) and sodium borohydride (24 mg) wereadded to a stirred solution of(±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanone oxime (50 mg) inmethanol (2 ml). After 0.5 hr, water was added until effervescenceceased, the reaction mixture was filtered, and the residue was washedthoroughly with methanol. The combined filtrate and washings wereevaporated in vacuo and the crude residue was purified by flash columnchromatography (SiO₂, dichloromethane/methanol, 9:1 v/v) to furnish thetitle compound as a colourless oil (31 mg, 65%) and a mixture ofdiastereoisomers; m/z (ES⁺) 295 (M+H)⁺.

Intermediate 11(±)-N-{3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexyl}methanesulfonamide

Triethylamine (0.014 ml) and methanesulfonyl chloride (8 μl) were addedto a solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexylamine(27 mg) in dichloromethane (1 ml), and the mixture was stirred underargon at ambient temperature. After 1 hr, the mixture was partitionedbetween ethyl acetate (20 ml) and sodium hydrogen carbonate (20 ml of asaturated aqueous solution). The aqueous layer was extracted with ethylacetate (2×20 ml), and the combined organic extracts were dried overmagnesium sulfate and evaporated in vacuo to furnish the title compoundas an oil and a mixture of diastereoisomers; m/z (ES⁺) 374 (M+H)⁺.

Intermediate 12(±)-2,4-Bis(methoxymethoxy)-1-(3-methylenecyclohexyl)benzene

Potassium tert-butoxide (50 mg) was added to a suspension ofmethyltriphenylphosphonium bromide in tetrahydrofuran (4 ml) at 0° C.After 0.5 hr, a solution of(±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanone (100 mg) intetrahydrofuran (1 ml) was added, and the mixture was allowed to warm toambient temperature. After 16 hr, the reaction mixture was partitionedbetween ammonium chloride (30 ml of a saturated aqueous solution) andethyl acetate. The aqueous layer was extracted with further ethylacetate (2×30 ml), and the combined organic extracts were washed withbrine (30 ml), dried over magnesium sulfate, and evaporated in vacuo.The crude residue was purified by flash column chromatography (SiO₂,ethyl acetate/petrol, 4:1 v/v) to furnish the title compound as paleyellow oil (80 mg, 81%). δ_(H)(CDCl₃) 1.50 (2H, m), 1.90 (2H, m), 2.05(1H, m), 2.16 (1H, m), 2.35 (1H, m), 2.44 (1H, m), 2.97 (1H, m), 3.44(3H, s), 3.48 (3H, s), 4.64 (1H, s), 4.69 (1H, s), 5.13 (2H, s), 5.17(2H, s), 6.68 (1H, m), 6.77 (1H, m), 7.12 (1H, d).

Intermediate 13(±)-{3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexyl}methanol

9-Borabicyclononane (2.7 ml of a 0.5M solution in tetrahydrofuran) wasadded to a stirred solution of(±)-2,4-bis(methoxymethoxy)-1-(3-methylenecyclohexyl)benzene (80 mg) intetrahydrofuran (2 ml) at 0° C. under argon. After 1 hr at 0° C., thereaction mixture was allowed to warm to ambient temperature and stirringcontinued. After 2 hr, the reaction mixture was cooled to 0° C. andwater (0.1 ml) was added. After the effervescence had subsided, hydrogenperoxide (1 ml of a 30% w/v solution) and sodium hydroxide (1 ml of a 2Msolution) were added and the mixture was allowed to warm to ambienttemperature. After a further 16 hr, the reaction mixture was cooled to0° C. Saturated aqueous sodium metabisulfite was added until no oxidantcould be detected by starch iodide paper, and the reaction mixture wasextracted with ethyl acetate (3×30 ml). The combined organic extractswere washed with water (20 ml), dried over magnesium sulfate, andevaporated in vacuo. The crude residue was purified by flash columnchromatography (SiO₂, ethyl acetate/petrol, 1:1 v/v) to furnish thetitle compound as a pale brown oil (46 mg, 54%); m/z (ES⁺) 311 (M+H)⁺.

Intermediate 14 (±)-3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexanone Oxime

Hydroxylamine hydrochloride (71 mg), triethylamine (0.17 ml) and(±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanone (200 mg) were heatedunder reflux in ethanol (8 ml). After 0.75 hr, the reaction mixture wasevaporated in vacuo and the residue was partitioned between ethylacetate (100 ml) and water (100 ml). The aqueous layer was extractedwith ethyl acetate (2×100 ml), and the combined organic extracts weredried over magnesium sulfate and evaporated in vacuo. The crude residuewas purified by flash column chromatography (SiO₂, ethyl acetate/petrol,1:1 v/v) to furnish the title compound as a pale yellow oil (197 mg,94%); m/z (ES⁺) 310 (M+H)⁺.

Intermediate 15 (±)-N-{3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexyl}hydroxylamine

Borane (0.412 ml of a 1M solution in tetrahydrofuran) was added to astirred solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanoneoxime (85 mg) in tetrahydrofuran (2 ml) at 0° C. under argon. After 2hr, acetic acid (1 ml) was added and the mixture was allowed to warm toambient temperature. After 16 hr, sodium hydrogen carbonate (20 ml of asaturated aqueous solution) was added, the mixture was extracted withethyl acetate (3×20 ml) and the combined organic extracts were driedover magnesium sulfate and evaporated in vacuo. The crude residue waspurified by flash column chromatography (SiO₂, dichloromethane/methanol,9:1 v/v) to furnish two compounds as clear gums which were identified asdiastereoisomers of the title compound; trans-isomer (12 mg, 14%) m/z(ES⁺) 312 (M+H)⁺; cis-isomer (0.017 g, 20%) m/z (ES⁺) 312 (M+H)⁺.

Intermediate 164-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone

4-(2,4-Dihydroxyphenyl)cyclohexanone (400 mg) was dissolved in dimethylformamide (3 ml) with stirring. tert-Butyldimethylsilyl chloride (704mg), imidazole (660 mg) and 4-dimethylaminopyridine (3 mg) were addedsequentially. After 4 hr, the solvent was removed in vacuo and theresidue partitioned between ethyl acetate (20 ml) and water (5 ml). Theaqueous phase was extracted with ethyl acetate (2×10 ml), and thecombined organic phases were washed with brine (10 ml), dried overanhydrous magnesium sulphate, and concentrated under reduced pressure togive a brown oil. Purification via flash column chromatography (SiO₂eluting with ethyl acetate/petroleum ether, 1:9 v/v) furnished the titlecompound as white flakes (750 mg, 89%). δ_(H)(CDCl₃): 0.18 (6H, s), 0.20(6H, s), 0.97 (9H, s), 1.03 (9H, s), 1.72-1.87 (2H, m), 2.15-2.17 (2H,m), 2.42-2.48 (4H, m), 3.33 (1H, tt), 6.32 (1H, d), 6.39 (1H, dd), 6.94(1H, d); m/z (ES⁺) 435 (M+1)⁺.

Intermediate 17 tert-Butyl[3-{[tert-butyl(dimethyl)silyl]oxy}-4-(4-methylenecyclohexyl)phenoxy]dimethylSilane

To a stirred suspension of methyltriphenylphosphonium bromide (329 mg)in anhydrous THF (10 ml) at 0° C. was added potassium tert-butoxide (103mg) in one portion. After stirring for 30 min, a solution of4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexanone (200 mg)in THF (5 ml) was added. The reaction mixture was stirred for a further30 min at 0° C., and saturated aqueous ammonium chloride solution (20ml) was added. The layers were separated and the aqueous layer extractedwith ethyl acetate (3×20 ml). The combined organic phases were washedwith brine (20 ml), dried over anhydrous magnesium sulphate, andconcentrated in vacuo. Purification via flash column chromatography(SiO₂ eluting with diethyl ether:petroleum ether, 1:4 v/v) furnished thetitle compound as a colourless oil (135 mg, 68%). δ_(H)(CDCl₃): 0.19(6H, s), 0.24 (6H, s), 0.97 (9H, s), 1.03 (9H, s), 1.41 (2H, dq),1.84-1.93 (2H, m), 2.16 (2H, dt), 2.33-2.42 (2H, m), 3.01 (1H, tt), 4.66(2H, s), 6.29 (1H, dd), 6.40 (1H, dd), 6.94 (1H, d).

Intermediate 18trans/cis-[4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]methanol

tert-Butyl[3-{[tert-butyl(dimethyl)silyl]oxy}-4-(4-methylenecyclohexyl)phenoxy]dimethylsilane (135 mg) was dissolved in anhydrous THF (5 ml) with stirring andcooled to −78° C. 9-Borabicyclo[3.3.1]nonane (3.13 ml, 0.5M in THF) wasadded to the stirred solution and the resulting reaction mixture allowedto warm to room temperature over 3 hr and then stirred for 3 days.Cooling to 0° C. was followed by addition of hydrogen peroxide (1 ml,30% aqueous solution) and sodium hydroxide (1 ml, 2M aqueous solution).The reaction mixture was allowed to warm to room temperature withstirring over 1 hr. cooled to 0° C., and saturated aqueous sodiummetabisulphate solution (30 ml) was added. The layers were separated andthe aqueous layer extracted with ethyl acetate (3×20 ml). The combinedorganic phases were washed with brine (20 ml), dried over anhydrousmagnesium sulphate, and concentrated in vacuo. Purification via flashcolumn chromatography (SiO₂ eluting with petroleum ether:diethyl ether,3:17 v/v) afforded the desired product as a yellow oil (73 mg, 52%).δ_(H)(CDCl₃): 0.18 (6H, s), 0.22 (6H, s), 0.97 (9H, s), 1.00 (9H, s),1.03-1.15 (0.5H, m), 1.22-1.33 (0.5H, m), 1.43-1.61 (4H, m), 1.77-1.94(4H, m), 2.75-2.92 (1H, m), 3.47 (1H, d), 3.70 (1H, d), 6.26-6.29 (1H,m), 6.37-6.40 (1H, m), 6.93-6.97 (1H, m).

Intermediate 19trans/cis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methylcyclohexanol

4-(2,4-Bis(tert-butyldimethylsilyloxy))phenylcyclohexanone (50 mg) wasdissolved in anhydrous THF (10 ml) and cooled to 0° C. Methylmagnesiumchloride (59 ml, 22% w/v in THF) was added dropwise and the reactionmixture allowed to warm to room temperature with stirring over 2 days.The reaction mixture was partitioned between aqueous HCl (10 ml, 0.5M)and ethyl acetate (10 ml). The aqueous phase was extracted with ethylacetate (2×10 ml) and the combined organic phases were washed withsaturated aqueous sodium bicarbonate solution (10 ml), brine (10 ml),and then dried over anhydrous magnesium sulphate. Removal of the solventunder reduced pressure afforded an oil which was purified via flashcolumn chromatography (SiO₂ eluting with ethyl acetate:petroleum ether,1:4 v/v) affording the title compound as a white solid and a mixture ofdiastereoisomers (29 mg, 56%). δ_(H)(CDCl₃): 0.19 (6H, s), 0.23 (6H, s),0.97 (9H, s), 1.02 (9H, s), 1.26 (1.5H, s), 1.32 (1.5H, s), 1.36-1.82(8H, m), 2.73-2.91 (1H, m), 6.29-6.31 (1H, m), 6.39-6.42 (1H, m), 6.80(0.5H, d), 7.20 (0.5H, d).

Intermediate 20trans/cis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine

4-[2,4-Bis(tert-butyldimethylsilyloxy)phenyl]cyclohexanone oxime (120mg) was dissolved in anhydrous methanol (10 ml) with stirring. Thesolution was cooled to −40° C., and nickel chloride hexahydrate (133 mg)was added. Stirring was continued for 10 min before sodium borohydride(42 mg) was added in one portion. The reaction mixture was stirred at−40° C. for 20 min and water (0.5 ml) was added. The reaction mixturewas allowed to warm to room temperature with stirring. Silica gel wasadded and the solvent removed in vacuo. Purification via flash columnchromatography (SiO₂ eluting with CH₂Cl₂:MeOH:NH₄OH, 44:50:6 v/v)afforded the desired product as a pale brown oil (83 mg, 71%) and amixture of diastereoisomers. δ_(H)(CD₃OD): 0.22 (6H, s), 0.27 (6H, s),1.02 (9H, s), 1.08 (9H, s), 1.24-1.40 (1H, m), 1.42-1.57 (1H, m),1.57-1.68 (1H, m), 1.71-1.90 (4H, m), 1.99-2.07 (1H, m), 2.84-2.98 (1H,m), 4.28-4.40 (1H, m), 6.34 (1H, d), 6.44 (1H, t), 7.04 (0.5H, d), 7.16(0.5H, d); m/z (ES⁺) 436 (M+1)⁺.

Intermediate 21trans/cis-N-[4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]acetamide

trans/cis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine(27 mg) was dissolved in pyridine (0.5 ml). Acetyl chloride (6 μl) and4-dimethylaminopyridine (2 mg) were added sequentially and the reactionmixture stirred for 24 hr. The solvent was removed in vacuo and theresidue partitioned between ethyl acetate (10 ml) and water (2 ml). Theaqueous phase was extracted with ethyl acetate (2×5 ml) and the combinedorganic phases were washed with brine (10 ml), dried over anhydrousmagnesium sulphate, and concentrated to give a brown oil. Purificationvia flash column chromatography (SiO₂ eluting with ethylacetate:petroleum ether, 7:3 v/v) afforded the title product as a whitesolid (15 mg, 50%) and a mixture of diastereoisomers. δ_(H)(CDCl₃): 0.17(3H, s), 0.19 (3H, s), 0.21 (3H, s), 0.22 (3H, s), 0.96 (9H, s), 1.02(9H, s), 1.06-1.20 (2H, m), 1.36-1.54 (2H, m), 1.60-1.75 (2H, m), 1.80-1.92 (2H, m), 1.95 (1.5H, s), 2.00 (1.5H, s), 2.75-2.90 (1H, m),3.76-3.87 (1H, m), 5.34-5.39 (0.5H, d), 5.72-5.77 (0.5H, d), 6.26-6.29(1H, m), 6.38-6.41 (1H, m), 6.93 (0.5H, d), 6.95 (0.5H, d); m/z (ES⁺)478 (M+1)⁺.

Intermediate 22 3-[2,4-Bis(methoxymethoxy)phenyl]-2-cyclopenten-1-one

1,3-Bis(methoxymethoxy)-4-bromobenzene (1.0 g) was dissolved in THF (20ml) and cooled to −78° C. under argon. N,N,N′,N′-Tetramethylethylenediamine was added followed by dropwise addition of n-BuLi (3.4 ml of a2.2M solution in hexanes) over 10 mins. After stirring at −78° C. for 1hr, a solution of 3-methoxy-2-cyclopentene-1-one (605 mg) in THF (5 ml)was added slowly. The reaction mixture was stirred at −78° C. for 1 hrbefore warming to 0° C. 1 M HCl (20 ml) was added, and after 10 min themixture was extracted with ethyl acetate (2×50 ml). The combined organicphases were washed with brine (30 ml), dried over magnesium sulfate, andconcentrated in vacuo. The crude residue was purified by flash columnchromatography (SiO₂, ethyl acetate/petrol, 1:1 v/v) to furnish thetitle compound as yellow oil (128 mg, 13%); m/z (ES⁺) 279 (M+1)⁺.

Intermediate 23 (±)-3-[2,4-Bis(methoxymethoxy)phenyl]cyclopentanone

3-[2,4-Bis(methoxymethoxy)phenyl]-2-cyclopenten-1-one (50 mg) andpalladium (10 mg, 10% on carbon) were stirred under an atmosphere ofhydrogen for 15 hr. The mixture was then filtered through a plug ofCelite, washing with ethyl acetate, and the filtrate was concentrated invacuo. The residue was purified by flash column chromatography (SiO₂,ethyl acetate/petrol, 1:1 v/v) to furnish the title compound as acolourless oil (8 mg, 16%); m/z (ES⁺) 583 (2M+Na)⁺.

Intermediate 24 3-(Benzyloxy)-2-cyclohexen-1-one

To a round bottomed flask equipped with magnetic stirrer and Dean-Starkapparatus was added 1,3-cyclohexanedione (60.0 g, 535 mmol), toluene(450 ml), p-toluenesulfonic acid monohydrate (1.35 g, 5.20 mmol) andbenzyl alcohol (52.6 g, 487 mmol). The resulting solution was heated toreflux temperature for 12 hr. The reaction mixture was cooled to roomtemperature and then washed with saturated aqueous sodium carbonatesolution (2×100 ml). The organic layer was then washed with brine (100ml), dried over magnesium sulfate, filtered and concentrated in vacuo,affording a brown oil (94.9 g) which crystallised upon standing for 17hr. The crude crystalline material was slurried in isopropyl ether (20ml). The mixture was filtered and the crystalline material was washedwith ice cold isopropyl ether (3×30 ml), then with cold petroleum ether(2×20 ml). The resulting peach coloured crystalline solid was driedovernight under reduced pressure, furnishing the desired product (74.4g, 76%). m/z (ES⁺) 203 (M+H⁺).

Intermediate 25(±)-3-(Benzyloxy)-6-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-2-cyclohexen-1-one

To a round bottomed flask equipped with magnetic stirrer was addedanhydrous tetrahydrofuran (600 ml) and diisopropylamine (38.1 ml, 272mmol). The stirred solution was cooled to −78° C. and n-butyl lithium(113.4 ml, 272 mmol, 2.4M in cyclohexanes) was added dropwise viasyringe in 20 ml portions. The resulting yellow solution was stirred for35 min at −78° C., then 3-(benzyloxy)-2-cyclohexen-1-one (50.0 g, 248mmol) was added as a solution in anhydrous tetrahydrofuran (100 ml). Thesolution was stirred for 1 hr prior to the addition ofcyclohexane-1,4-dione monoethylene ketal (38.7 g, 248 mmol) as asolution in anhydrous tetrahydrofuran (100 ml). The solution was stirredfor 2 hr at −78° C., then allowed to warm slowly to room temperatureover 1 hr. Saturated aqueous ammonium chloride (80 ml) was added,followed by dichloromethane (700 ml), and the mixture was stirred untilno solids remained. The layers were separated and the aqueous phaseextracted with dichloromethane (2×100 ml). The combined organic layerswere washed with brine (50 ml), dried over magnesium sulfate, thenconcentrated in vacuo. Trituration of the resulting solid with methanolafforded the title compound (78.4 g, 88%). m/z (ES⁺) 359 (M+H⁺).

Intermediate 26(±)-1-(Benzyloxy)-6-bromo-3-(1,4-dioxaspiro[4.5]dec-8-yl)-2-oxabicyclo[2.2.2]octan-5-one

A round bottomed flask equipped with magnetic stirrer was charged with(±)-3-(benzyloxy)-6-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-2-cyclohexen-1-one(78.4 g, 219 mmol) and dichloromethane (600 ml). To the stirred solutionwas added N-bromosuccinimide (40.9 g, 230 mmol) in one portion, followedby aqueous hydrobromic acid (3 drops, 48% solution) when no more solidremained. The resulting solution was stirred at room temperature for 2hr then poured into a separating funnel containing aqueous sodiummetabisulfite solution (150 ml) and dichloromethane (200 ml), then thefunnel was shaken vigorously. The layers were separated and the organiclayer was washed with brine (200 ml), dried over magnesium sulfate,filtered, then concentrated in vacuo to give a solid. Trituration withmethanol (500 ml) afforded the desired compound (82.8 g, 86%) as a whitesolid. m/z (ES⁺) 437 and 439 [(1:1), M+H⁺].

Intermediate 27 5-(Benzyloxy)-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenol

A round bottomed flask was charged with(±)-1-(benzyloxy)-6-bromo-3-(1,4-dioxaspiro[4.5]dec-8-yl)-2-oxabicyclo[2.2.2]octan-5-one(13.8 g, 31.6 mmol) and anhydrous N,N-dimethylformamide (140 ml). To thestirred solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (9.92 ml,66.3 mmol) in one portion. The solution turned dark brown in colourimmediately and was then heated to 140° C. for 12 hr with vigorousstirring. The reaction mixture was allowed to cool to room temperatureand most of the solvent was removed under reduced pressure. Theremaining oil was partitioned between ethyl acetate (200 ml) and water(100 ml), then the layers were separated and the aqueous phase wasextracted with ethyl acetate (3×50 ml). The combined organic layers wereback extracted with water (3×30 ml) to remove any residualN,N-dimethylformamide. The organic phase was washed with brine (20 ml),dried over magnesium sulfate, filtered and concentrated in vacuo toafford a brown oily solid, which was adsorbed onto silica gel.Purification via flash column chromatography (SiO₂, ethylacetate/petroleum ether, 1:1, v/v) furnished the desired product (7.1 g,66%) as a white solid. m/z (ES⁺) 339(M+H⁺).

Intermediate 28 4-(1,4-Dioxaspiro[4.5]dec-8-yl)-1,3-benzenediol

A round bottomed flask equipped with magnetic stirrer was charged with5-(benzyloxy)-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenol (6.90 g, 20.4mmol), ethanol (300 ml) and palladium (2.00 g, 10% on activated carbon).The reaction vessel was then evacuated and placed under a hydrogenatmosphere. This process was repeated 15 times before stirringvigorously for 64 hr under a hydrogen atmosphere. The reaction mixturewas filtered through a celite plug, washing with ethyl acetate. Thefiltrate was concentrated in vacuo, furnishing the title compound (5.10g, 100%) as a solid. m/z(ES⁺) 251(M+H⁺).

Intermediate 29cis-N-Benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]amine

To a round bottomed flask equipped with magnetic stirrer was loaded4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone (3.20 g,7.36 mmol). Anhydrous 1,2-dichloroethane (85 ml) was added, and to thestirred solution was added benzylamine (0.97 ml, 8.83 mmol) as asolution in 1,2-dichloroethane (20 ml). Activated powdered 4 Å molecularsieves (5.80 g) were added and the reaction mixture stirred vigorouslyfor 2.5 hr. Tetramethylammoniumtriacetoxyborohydride (2.90 g, 11.0 mmol)was added in one portion and the reaction mixture stirred for 64 hr atroom temperature. Aqueous sodium hydroxide solution (30 ml, 0.4M) wasadded and vigorous stirring was continued for 0.5 hr. The reactionmixture was then filtered through celite, washing with dichloromethane(100 ml). The layers were separated and the aqueous layer was extractedwith dichloromethane (2×50 ml). The combined organic phases were washedwith brine (100 ml), dried over magnesium sulfate, filtered andconcentrated in vacuo affording the crude product. Purification viaflash column chromatography (SiO₂, ethyl acetate/petroleum ether,gradient elution using 1:9, 1:4, then 3:7 v/v) furnished the titleproduct (2.69 g, 70%) as a pale yellow oil. δ_(H)(CDCl₃) 0.01 (6H, s),0.05 (6H, s), 0.77 (9H, s), 0.83 (9H, s), 1.31 (1H, br), 1.39 (4H, m),1.52 (2H, m), 1.70 (2H, m), 2.69 (1H, m), 2.75 (1H, m), 6.10 (1H, d),6.23 (1H, dd), 6.84 (1H, d), 7.15 (5H, m).

Intermediate 30N-Benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylidene]amine

To a round bottomed flask equipped with magnetic stirrer was added4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone (817 mg,1.88 mmol). Anhydrous dichloromethane (50 ml) was added followed bybenzylamine (0.82 ml, 7.52 mmol) and activated 4 Å molecular sieves(10.0 g). The reaction mixture was stirred vigorously for 15 hr, thendichloromethane (50 ml) was added and the reaction mixture filteredthrough celite, washing with dichloromethane (50 ml). The filtrate wasconcentrated in vacuo affording the desired product (1.00 g, 86%) as ayellow oil. δ_(H)(CDCl₃) 0.19 (6H, s), 0.26 (6H, s), 0.98 (9H, s), 1.03(9H, s), 1.51 (1H, m), 1.72 (1H, m), 2.03 (2H, m), 2.45 (1H, m), 2.60(1H, m), 3.04 (1H, m), 3.22 (1H, m), 4.55 (1H, d), 4.60 (1H, d), 6.31(1H, d), 6.41 (1H, dd), 6.93 (1H, d), 7.33 (5H, m).

Intermediate 31trans-N-Benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy} phenyl)cyclohexyl]amine

To a round bottomed flask equipped with magnetic stirrer was addedN-benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylidene]amine(4.00 g, 7.63 mmol) and anhydrous tetrahydrofuran (480 ml) followed byanhydrous methanol (120 ml). To the solution was added sodiumborohydride (1.16 g, 30.5 mmol) and the reaction mixture stirred for 17hr. The reaction mixture was then diluted with diethyl ether (600 ml)and aqueous sodium hydroxide (400 ml, 0.4M) was added. After stirringfor 10 min, the layers were separated and the aqueous layer extractedwith dichloromethane (3×100 ml). The combined organic phases were washedwith brine (50 ml), dried over magnesium sulfate and concentrated invacuo to give a yellow oil. Purification via flash column chromatography(SiO₂, ethyl acetate/petroleum ether, gradient elution using 1:9, 1:4,then 3:7, v/v) furnished the desired product as a cream coloured solid(2.09 g, 54%). δ_(H)(CDCl₃) 0.01 (6H, s), 0.05 (6H, s), 0.80 (9H, s),0.85 (9H, s), 1.18 (4H, m), 1.66 (2H, m), 1.87 (2H, m), 2.19 (1H, m),2.68 (1H, M), 6.12 (1H, d), 6.23 (1H, dd), 6.77 (1H, d), 7.17 (5H, m).

Intermediate 32trans-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine

To a round bottom flask was addedtrans-N-benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy} phenyl)cyclohexyl]amine (500 mg, 0.95 mmol) and ethanol (20 ml). To the stirredsolution was added palladium (10% w/w on activated carbon, 200 mg, 0.19mmol) as a slurry in ethanol (5 ml). The reaction vessel was evacuated,then placed under hydrogen (10 cycles). The reaction mixture was stirredvigorously under an atmosphere of hydrogen for 18 hr, then filteredthrough a celite plug, washing with methanol (100 ml). The solvent wasremoved in vacuo affording the desired product (402 mg, 97%) as acolourless oil. δ_(H)(CDCl₃) 0.01 (6H, s), 0.05 (6H, s), 0.78 (9H, s),0.82 (9H, s), 1.08 (2H, m), 1.21 (2H, m), 1.62 (2H, m), 1.78 (2H, m),2.59 (2H, m), 6.11 (1H, d), 6.22 (1H, dd), 6.78 (1H, d).

Intermediate 33cis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine

To a round bottom flask equipped with magnetic stirrer was addedcis-N-benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]amine(700 mg, 1.33 mmol) and ethanol (30 ml). To the stirred solution wasadded palladium (10% w/w on activated carbon, 283 mg, 0.27 mmol) as aslurry in ethanol (5 ml). The reaction vessel was evacuated then placedunder hydrogen (10 cycles). The reaction mixture was stirred vigorouslyunder an atmosphere of hydrogen for 18 hr then filtered through a celiteplug, washing with methanol (100 ml). The solvent was removed in vacuoaffording the desired product (561 mg, 97%) as a colourless oil.δ_(H)(CDCl₃) 0.01 (6H, s), 0.04 (6H, s), 0.78 (9H, s), 0.83 (9H, s),1.21-1.55 (10H, m), 2.64 (1H, m), 3.05 (1H, m), 6.11 (1H, d), 6.22 (1H,dd), 6.84 (1H, d).

Intermediate 34cis-N-[4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]Methane Sulfonamide

A round bottomed flask equipped with magnetic stirrer was charged withcis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine (47mg, 0.108 mmol) and 1,2-dichloroethane (4 ml). To the stirred solutionwas added methanesulfonyl chloride (10 μl, 0.12 mmol), triethylamine (30μl, 0.22 mmol) and 4-dimethylaminopyridine (catalytic amount). Thesolution was stirred for 17 hr then partitioned between aqueous sodiumhydroxide (5 ml, 0.2M) and dichloromethane (5 ml). The aqueous phase wasextracted with dichloromethane (2×5 ml) and the combined organic layerswere washed with brine (8 ml), dried over magnesium sulfate andconcentrated in vacuo. The crude product was adsorbed onto silica geland purified via flash column chromatography (SiO₂, ethylacetate/petroleum ether, gradient elution using 1:9, 1:4, then 1:3, v/v)to give the title compound (39 mg, 70%) which solidified on standing.δ_(H)(CDCl₃) 0.17 (6H, s), 0.23 (6H, s), 0.97 (9H, s), 1.00 (9H, s),1.53 (2H, m), 1.71 (4H, m), 1.94 (2H, m), 2.85 (1H, m), 2.99 (3H, s),3.78 (1H, m), 4.83 (1H, d), 6.28 (1H, d), 6.42 (1H, dd), 6.97 (1H, d).

Intermediate 35trans-N-[4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]Methane Sulfonamide

To a round bottomed flask equipped with magnetic stirrer was addedtrans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine(248 mg, 0.57 mmol) and 1,2-dichloroethane (25 ml). To the stirredsolution was added triethylamine (191 μl, 1.37 mmol) followed bymethanesulfonyl chloride (53 μl, 0.68 mmol) and three crystals of4-dimethylaminopyridine. The resulting solution was stirred at roomtemperature for 18 hr and then poured into a separating funnelcontaining dichloromethane (100 ml) and water (20 ml). The layers wereseparated and the aqueous phase extracted with dichloromethane (1×50ml). The combined organic phases were washed with brine (50 ml), driedover magnesium sulfate, filtered and concentrated in vacuo affording thetitle compound as a pale yellow oil (320 mg, 100%). δ_(H)(CDCl₃) 0.02(6H, s), 0.05 (6H, s), 0.78 (9H, s), 0.82 (9H, s), 1.22 (4H, m), 1.70(2H, m), 1.99 (2H, m), 2.61 (1H, m), 2.81 (3H, s), 3.19 (1H, m), 3.92(1H, d), 6.13 (1H, d), 6.22 (11H, dd), 6.66 (1H, d).

Intermediate 364-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone

To a round bottomed flask equipped with magnetic stirrer was added4-(4-hydroxy)phenylcyclohexanone (1.00 g, 5.26 mmol) (commerciallyavailable from Aldrich) and anhydrous N,N-dimethylformamide (5 ml). Tothe stirred solution was added imidazole (0.90 g, 13.20 mmol),tert-butyl(dimethyl)silyl chloride (1.19 g, 7.89 mmol) and4-dimethylaminopyridine (catalytic amount). The reaction mixture wasstirred for 17 hr at room temperature and then the N,N-dimethylformamideremoved in vacuo. The residue was partitioned between ethyl acetate (100ml) and water (5 ml). The layers were separated and the aqueous phasewas extracted with ethyl acetate (3×20 ml). The combined organic layerswere washed with brine, dried over magnesium sulfate, filtered andconcentrated in vacuo. Purification via flash column chromatography(SiO₂, ethyl acetate/petroleum ether, 2:3, v/v) afforded the titlecompound (1.39 g, 87%) as a pale yellow solid. δ_(H)(CDCl₃) 0.19 (6H,s), 0.98 (9H, s), 1.87 (2H, m), 2.20 (2H, m), 2.46 (4H, m), 2.99 (1H,m), 6.77 (2H, d), 7.07 (2H, d).

Intermediate 374-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-1-[2,4-bis(methoxymethoxy)phenyl]cyclohexanol

A round bottomed flask equipped with magnetic stirrer was charged with1-bromo-2,4-bis(methoxymethoxy)benzene (277 mg, 1.00 mmol) and anhydroustetrahydrofuran (5 ml). The stirred solution was cooled to −78° C. andN,N,N′,N′-tetramethylethylene diamine (0.32 ml, 2.10 mmol) was addedfollowed by dropwise addition of n-butyl lithium (0.88 ml, 2.10 mmol,2.40M solution in cyclohexanes). The resulting solution was stirred for40 min at −78° C., then 4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone (304 mg, 1.00 mmol) was added via syringe as a solution inanhydrous tetrahydrofuran (2 ml) and the reaction mixture stirred for 30min at −78° C., then allowed to warm to room temperature over 3 hr. Thereaction was quenched with aqueous hydrochloric acid (5 ml, 0.10M), thenpoured into a separating funnel containing ethyl acetate (50 ml) andwater (10 ml). The layers were separated and the aqueous phase extractedwith ethyl acetate (3×5 ml). The combined organic layers were washedwith brine (10 ml), dried over magnesium sulfate, filtered andconcentrated in vacuo. The resulting oil was purified via flash columnchromatography (SiO₂, ethyl acetate/petroleum ether, 3:7, v/v)furnishing the title compound as a white solid (127 mg, 25%) and amixture of diastereoisomers. δ_(H)(CDCl₃) 0.19 (6H, s), 0.98 (6H, s),1.63 (2H, m), 1.84 (2H, m), 1.96 (2H, m), 2.56 (2H, m), 2.70 (1H, m),3.48 (3H, s), 3.49 (3H, s), 3.85 (1H, s), 5.15 (2H, s), 5.24 (2H, s),6.68 (1H, dd), 6.73 (2H, d), 6.85 (1H, d), 7.05 (2H, d), 7.33 (1H, d).

Intermediate 38 tert-Butyl(4-{4-[2,4-bis(methoxymethoxy)phenyl]-3-cyclohexen-1-yl}phenoxy)dimethylsilane

A round bottomed flask equipped with magnetic stirrer was charged with4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-[2,4-bis(methoxymethoxy)phenyl]cyclohexanol (125 mg, 0.25 mmol), toluene (10 ml) and p-toluenesulfonic acid monohydrate (3 crystals). The reaction mixture was heatedto reflux temperature for 30 min, then cooled to room temperature beforeadding saturated aqueous sodium bicarbonate (5 ml). The layers wereseparated and the aqueous layer was extracted with ethyl acetate (3×10ml). The combined organic layers were washed with brine (10 ml), driedover magnesium sulfate, filtered and concentrated in vacuo. The titlecompound was isolated without further purification as an oil (118 mg,98%) and a mixture of diastereoisomers. δ_(H)(CDCl₃) 0.19 (6H, s), 0.98(9H, s), 1.84 (1H, m), 2.00 (1H, m), 2.27 (1H, m), 2.44 (2H, m), 2.56(1H, m), 3.48 (3H, s), 3.49 (3H, s), 5.15 (2×2H, s), 5.79 (1H, m), 6.67(1H, dd), 6.77 (2H, d), 6.78 (1H, d), 7.07 (2H, d), 7.11 (1H, d).

Intermediate 39 tert-Butyl(4-{4-[2,4-bis(methoxymethoxy)phenyl]cyclohexyl}phenoxy) Dimethyl Silane

To a round bottomed flask equipped with magnetic stirrer was addedtert-butyl(4-{4-[2,4-bis(methoxymethoxy)phenyl]-3-cyclohexen-1-yl}phenoxy)dimethylsilane (118 mg, 0.24 mmol) and ethanol (15 ml). To the stirredsolution, palladium (catalytic amount, 10% on activated carbon) wasadded in one portion. The reaction vessel was then evacuated and placedunder an atmosphere of hydrogen. This process was repeated for 10 cyclesbefore leaving under a hydrogen atmosphere. The reaction mixture wasstirred vigorously for 17 hr then filtered through celite, washing withethyl acetate. The filtrate was concentrated in vacuo affording thetitle compound as a colourless oil (118 mg, 100%) and a mixture ofdiastereoisomers. δ_(H)(CDCl₃) 0.15 (6H, s), 0.92 (9H, s), 1.51 (2H, m),1.63 (2H, m), 1.81 (2H, m), 1.94 (2H, m), 2.43 and 2.90 (1H, m), 2.84and 3.02 (1H, m), 3.38 and 3.39 (3H, s), 3.40 (2×1.5H, s), 5.04 and 5.06(2H, s), 5.08 and 5.10 (2H, s), 6.56 and 6.61 (1H, m), 6.70 (3H, m),7.03 (2H, m), 7.11 (1H, d).

Intermediate 40 (±)-Methyl{4-[2,4-bis(methoxymethoxy)phenyl]cyclohexylidene}acetate

A round bottomed flask equipped with magnetic stirrer was loaded withsodium hydride (0.20 g, 5.10 mmol, 60% dispersion in mineral oil) whichwas washed with petroleum ether (4×20 ml). The excess petroleum etherwas removed under reduced pressure. Anhydrous tetrahydrofuran (120 ml)was added and the stirred solution was cooled to 0° C.Trimethylphosphonoacetate (756 μl, 5.10 mmol) was added dropwise viasyringe and the stirred mixture was allowed to warm to room temperatureover 1 hr. The mixture was cooled to 0° C. prior to the addition of4-[2,4-bis(methoxymethoxy)phenyl] cyclohexanone (1.00 g, 3.40 mmol) as asolution in tetrahydrofuran (30 ml). The pale yellow mixture was heatedto reflux temperature for 0.75 hr, then cooled to room temperature andpartitioned between ethyl acetate (100 ml) and saturated aqueousammonium chloride solution (30 ml). The layers were separated and theaqueous layer was extracted with ethyl acetate (3×30 ml). The combinedorganic layers were washed with brine (30 ml), dried over magnesiumsulfate, filtered and concentrated in vacuo, affording a yellow oil.Purification via flash column chromatography (SiO₂, ethylacetate/petroleum ether, 1:2, v/v) furnished the title compound as ayellow oil (1.13 g, 95%). δ_(H)(CD₃OD) 1.53-1.70 (2H, m), 2.00-2.13 (4H,m), 2.45 (2H, m), 3.26 (1H, m), 3.48 (3H, s), 3.53 (3H, s), 3.71 (3H,s), 5.17 (2H, s), 5.24 (2H, s), 5.73 (1H, s), 6.67 and 6.68 (1H, d),6.83 (1H, d), 7.08 (1H, d).

Intermediate 41 cis/trans-Methyl{4-[2,4-bis(methoxymethoxy)phenyl]cyclohexyl} acetate

To a round bottomed flask equipped with magnetic stirrer was added(±)-methyl {4-[2,4-bis(methoxymethoxy)phenyl]cyclohexylidene}acetate(1.13 g, 3.23 mmol) and ethanol (50 ml). To the stirred solution wasadded palladium (catalytic amount, 10% on activated carbon) in oneportion. The reaction vessel was evacuated and placed under anatmosphere of hydrogen. This process was repeated for 10 cycles beforeleaving under a hydrogen atmosphere and then stirred vigorously for 17hr. The reaction mixture was filtered through celite, washing withethanol and the filtrate was evaporated to dryness, furnishing the titlecompound (1.13 g, 99%) as a colourless oil and a mixture ofdiastereoisomers. δ_(H)(CD₃OD) 1.53 (2H, m), 1.62-1.78 (2H, m), 1.87(4H, m), 2.93 (1H, m), 3.47 (3H, s), 3.51 (3H, s), 3.71 and 3.72 (3H,s), 5.16 and 5.17 (2H, s), 5.22 and 5.23 (2H, s), 6.66 and 6.68 (1H, d),6.79 and 6.80 (1H, s), 7.12 and 7.15 (1H, d).

Intermediate 42(±)-{4-[2,4-Bis(methoxymethoxy)phenyl]cyclohexylidene}acetic Acid

To a round bottomed flask equipped with magnetic stirrer was addedtrimethylsilyidiethylphosphonoacetate (1.08 ml, 3.83 mmol) and anhydroustetrahydrofuran (25 ml). The stirred solution was cooled to 0° C. andn-butyl lithium (1.80 ml, 3.83 mmol, 2.2M in cyclohexanes) was addeddropwise, via syringe over 5 min. The reaction mixture was allowed towarm slowly to room temperature and stirred for 17 hr. 4-[(2,4-Bis(methoxymethoxy)phenyl)]cyclohexanone (750 mg, 2.55 mmol) was addedvia syringe as a solution in tetrahydrofuran (25 ml). After 2 hrstirring at room temperature, the reaction mixture was poured into aseparating funnel containing aqueous sodium hydroxide solution (10 ml,10% w/v). After extracting once with diethyl ether (10 ml), the aqueouslayer was acidified by adding concentrated hydrochloric acid (10 ml),then extracted with diethyl ether (3×20 ml). The combined organic layerswere washed with water (10 ml), dried over magnesium sulfate, filteredand concentrated in vacuo affording the title compound (422 mg, 52%) asan oil. δ_(H)(CDCl₃) 1.86 (2H, m), 2.00-2.13 (4H, m), 2.42 (2H, m), 3.19(1H, m), 3.48 (3H, s), 3.51 (3H, s), 5.14 (2H, s), 5.21 (2H, s), 5.71(1H, s), 6.67 (1H, dd), 6.81 (1H, d), 7.05 (1H, d).

Intermediate 43 (±)-{4-[2,4-Dihydroxyphenyl]cyclohexylidene}acetic Acid

A round bottomed flask equipped with magnetic stirrer was loaded with(±)-{4-[2,4-bis(methoxymethoxy)phenyl]cyclohexylidene}acetic acid (25mg, 74 μmol), acidic dowex resin (75 mg) and methanol (15 ml) thenstirred at 60° C. for 3 hr. The reaction mixture was filtered through acelite plug, washing with methanol. The solvent was removed underreduced pressure to give a yellow oil (15 mg) which was purified bypreparative TLC (ethyl acetate/petroleum ether, 3:1, v/v), furnishingthe title compound (6.5 mg, 35%) as an oil. m/z(ES⁺) 339 (M+H⁺).

Intermediate 44(±)-{4-[2,4-Bis(methoxymethoxy)phenyl]cyclohexylidene}acetonitrile

To a round bottomed flask equipped with magnetic stirrer was addedsodium hydride (40 mg, 0.95 mmol, 60% dispersion in mineral oil). Afterwashing the sodium hydride with petroleum ether (2×20 ml), the excesssolvent was removed under reduced pressure. 1,2-Dimethoxyethane (10 ml)was added and the stirred suspension cooled to 0° C. Diethylcyanomethylphosphonate (102 μl, 0.95 mmol) was added dropwise. Thereaction mixture was allowed to warm slowly to room temperature over 2hr. 4-[(2,4-Bis(methoxymethoxy)phenyl)]cyclohexanone (200 mg, 0.68 mmol)was then added as a solution in 1,2-dimethoxyethane (10 ml) and thereaction mixture stirred for 17 hr at room temperature. The reactionmixture was poured into a separating funnel containing water (50 ml) anddiethyl ether (50 ml). The layers were separated and the aqueous phaseextracted with diethyl ether (2×20 ml). The combined organic layers werewashed with brine (20 ml), dried over magnesium sulfate, filtered andconcentrated in vacuo, to give an oil. Purification via flash columnchromatography (SiO₂, ethyl acetate/petroleum ether, 1:2, v/v) affordedthe title compound (141 mg, 66%) as a pale yellow oil. δ_(H)(CD₃OD)1.57-1.70 (2H, m), 2.02-2.25 (2H, m), 2.34-2.49 (2H, m), 2.60 (1H, m),3.03 (1H, m), 3.24 (1H, m), 3.47 (3H, s), 3.52 (3H, s), 5.17 (2H, s),5.23(2H, s), 5.33 (1H, s), 6.66 and 6.69 (1H, d), 6.83 (1H, d), 7.09(1H, d

Intermediate 45(±)-[4)-(2,4-Dihydroxyphenyl)cyclohexylidene]acetonitrile

To a round bottomed flask equipped with magnetic stirrer was added(±)-{4-[2,4-bis(methoxymethoxy)phenyl]cyclohexylidene}acetonitrile (141mg, 0.45 mmol) and methanol (5 ml). The reaction mixture was stirred,the solution was heated to reflux temperature and aqueous hydrochloricacid (5 ml, 1.0M) was added slowly. Heating was continued for 1 hr andthe reaction mixture was allowed to cool to room temperature prior tothe addition of saturated aqueous sodium bicarbonate solution (12 ml).The reaction mixture was then partitioned between ethyl acetate (30 ml)and water (10 ml). The aqueous layer was extracted with ethyl acetate(3×15 ml) and the combined organic layers washed with brine (20 ml),dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified via flash column chromatography (SiO₂, ethylacetate/petroleum ether, 1:1, v/v) to afford the title compound as awhite solid (90 mg, 88%). m/z (ES⁻) 228 (M−H⁺); δ_(H)(CD₃OD) 1.56-1.68(2H, m), 2.02-2.14 (2H, m), 2.33-2.48 (2H, m), 2.57 (1H, m), 3.01 (1H,m), 3.14 (1H, m), 5.31 (1H, s), 6.26 and 6.28 (1H, d), 6.32 (1H, d),6.80 (1H, d).

Intermediate 46(±)-1-(3,3-Difluorocyclohexyl)-2,4-bis(methoxymethoxy)benzene

Diethylaminosulfur trifluoride (34 μl) was added to a stirred solutionof (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanone (40 mg) inanhydrous 1,2-dimethoxyethane at room temperature under argon. After 1hr further diethylaminosulfur trifluoride (170 μl) was added. After 48hr, the reaction mixture was partitioned between water (20 ml) and ethylacetate (20 ml). The aqueous layer was extracted with ethyl acetate(2×20 ml) and the combined organic extracts were dried over magnesiumsulfate and evaporated in vacuo. The crude residue was purified by flashcolumn chromatography (SiO₂, ethyl acetate/petrol, 1:1 v/v) to give thetitle compound as a gum (31 mg); m/z (ES⁺) 317 (M+H)⁺, R_(f) (ethylacetate/petrol, 1:1 v/v) 0.5.

Intermediate 47(±)-3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexanecarboxylic Acid

A solution of (±)-{3-[2,4-bis(methoxymethoxy)phenyl]cyclohexyl}methanol(50 mg) in acetone (1 ml) was added to a stirred solution of chromium(VI) oxide (64 mg) in 2M sulfuric acid (0.64 ml) at 0° C. over 3 hr.After 3 hr at 0° C. and then 16 hr at room temperature, the reactionmixture was partitioned between water (10 ml) and ethyl acetate (20 ml).The layers were separated and the aqueous layer was extracted with ethylacetate (2×20 ml). The combined organic extracts were washed with water(20 ml), dried over magnesium sulfate and evaporated in vacuo. Theresidue was purified by flash column chromatography (SiO₂, ethylacetate/petrol, 4:1 v/v) to give the title compound as a colourless oil(15 mg, 29%). R_(f) (ethyl acetate/petrol, 4:1 v/v) 0.5.

Intermediate 48(±)-3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexanecarboxamide

Triethylamine (16 μl) and isobutylchloroformate (14 μl) were added to astirred solution of(±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanecarboxylic acid inanhydrous tetrahydrofuran (2 ml) at 0° C. under argon. After 30 min,aqueous ammonia solution (0.5 ml, 28% w/w) was added. The reactionmixture was partitioned between water (20 ml) and ethyl acetate (50 ml).The aqueous layer was extracted with ethyl acetate (2×20 ml) and thecombined organic extracts were dried over magnesium sulfate andevaporated in vacuo to give the title compound (26 mg, 87%) as a mixtureof diastereoisomers; m/z (ES⁺) 324 (M+H)⁺.

Intermediate 49(±)-3-[2,4-Bis(methoxymethoxy)phenyl]-N-hydroxycyclohexanecarboxamide

Triethylamine (11 μl) and isobutylchloroformate (10 μl) were added to astirred solution of(±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanecarboxylic acid inanhydrous tetrahydrofuran (2 ml) at 0° C. under argon. After 30 min,aqueous hydroxylamine solution (0.5 ml, 50 wt %) was added. The reactionmixture was partitioned between water (20 ml) and ethyl acetate (50 ml).The aqueous layer was extracted with ethyl acetate (2×20 ml) and thecombined organic extracts were dried over magnesium sulfate andevaporated in vacuo to give the title compound as a solid (26 mg,quant.) and a mixture of diastereoisomers; m/z (ES⁺) 340 (M+H)⁺.

Intermediate 50(±)-3-[2,4-Bis(methoxymethoxy)phenyl]-N-ethylcyclohexanecarboxamide

Triethylamine (11 μl) and isobutylchloroformate (10 μl) were added to astirred solution of(±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanecarboxylic acid inanhydrous tetrahydrofuran (2 ml) under argon at 0° C. After 30 min,ethylamine (0.5 ml, 2M solution in tetrahydrofuran) was added. Thereaction mixture was partitioned between water (20 ml) and ethyl acetate(50 ml). The aqueous layer was extracted with ethyl acetate (2×20 ml)and the combined organic extracts were dried over magnesium sulfate andevaporated in vacuo to give the title compound as a solid (24 mg,quant.) and a mixture of diastereoisomers; m/z (ES⁺) 352 (M+H)⁺.

Intermediate 51(±)-3-[2,4-Bis(methoxymethoxy)phenyl]-1-(hydroxymethyl)cyclohexanol

N-Methyl morpholine N-oxide (120 mg) and osmium tetroxide (100 μl, 2.5wt % in tert-butanol) were added to a solution of(±)-2,4-bis(methoxymethoxy)-1-(3-methylenecyclohexyl) benzene (30 mg) intetrahydrofuran (0.7 ml) and water (0.3 ml) at room temperature. After16 hr, celite was added to the reaction mixture followed by water (5 ml)and sodium persulfite (20 mg). The reaction mixture was filtered, thefiltrate was adjusted to pH 4 with 2M hydrochloric acid solution and theaqueous volume was made up to 20 ml. The aqueous layer was extractedwith ethyl acetate (3×20 ml), the combined organic extracts were washedwith brine (20 ml), dried over magnesium sulfate and evaporated invacuo. The residue was purified by flash column chromatography (SiO₂,ethyl acetate) to give the title compound as a solid (30 mg, 89%) and amixture of diastereoisomers; m/z (ES⁺) 327 (M+H)⁺.

Intermediate 52(±)-N-{3-[2,4-bis(methoxymethoxy)phenyl]cyclohexyl}acetamide

Triethylamine (15 μl) and acetic anhydride (10 ml) were added to astirred solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexylamine(29 mg) in anhydrous 1,2-dichloroethane (2 ml) at room temperature.After 0.5 hr, the reaction mixture was partitioned between water (20 ml)and ethyl acetate (50 ml) and the aqueous layer was extracted with ethylacetate (3×20 ml). The combined organic extracts were dried overmagnesium sulfate and evaporated in vacuo to give the title compound asa solid (22 mg, 66%) and a mixture of diastereoisomers; m/z (ES⁺) 338(M+H)⁺.

Intermediates 53 and 54trans-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanolcis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol

Sodium borohydride (164 mg) was added to a stirred solution of4-(2,4-bis{(tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone (1.57 g)in ethanol (50 ml) at 0° C. After 2 hr at 0° C. and then 18 hr at roomtemperature, the reaction mixture was partitioned between 2M HCl (20ml), water (40 ml) and ethyl acetate (50 ml) and the aqueous layer wasre-extracted with ethyl acetate (2×50 ml). The combined organic extractswere washed with brine (40 ml), dried over magnesium sulfate andevaporated in vacuo. The residue was purified using flash columnchromatography (SiO₂, ethyl acetate/petrol, 3:17 v/v) to give thetrans-title compound as a white solid (546 mg, 35%), and the cis-titlecompounds as a white solid (83 mg, 5%).

trans-δ_(H)(CDCl₃) 0.18 (6H, s), 0.22 (6H, s), 0.98 (9H, s), 1.02 (9H,s), 1.18-1.22 (4H, m), 1.80-1.84 (3H, m), 2.00-2.05 (2H, m), 2.78-2.86(1H, m), 3.60-3.70 (1H, m), 6.28 (1H, d), 6.39 (1H, dd), 6.94 (1H, d).

cis-δ_(H)(CDCl₃) 0.18 (6H, s), 0.22 (6H, s), 0.98 (9H, s), 1.02 (9H, s),1.58-1.78 (6H, m), 1.84-1.92 (2H, m), 2.70-2.80 (1H, m), 4.12 (1H, bs),6.28 (1H, d), 6.40 (1H, dd), 7.02 (1H, d).

Intermediate 55trans-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl4-(dimethylamino) benzoate

Triethylamine (20 μl), 4-dimethylaminopyridine (catalytic amount) and4-dimethylaminobenzoyl chloride (26 mg) were added to a stirred solutionof trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol(30 mg) in dry dichloromethane (2 ml) at room temperature under argon.After 24 hr, the solvent was removed under reduced pressure and theresidue was partitioned between water (10 ml) and ethyl acetate (20 ml).The aqueous layer was extracted with ethyl acetate (2×20 ml) and thecombined organic extracts were washed with brine (10 ml), dried overmagnesium sulfate and evaporated in vacuo. The residue was purified byflash column chromatography (SiO₂, ethyl acetate/petrol, 1:24 v/v) togive the title compound as a white solid (18 mg, 45%); m/z (ES⁺) 585(M+H)⁺.

Intermediate 56cis/trans-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanecarboxylicAcid

Pyridinium dichromate (146 mg) was added to a stirred solution ofcis/trans-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]methanol(50 mg) in N,N-dimethylformamide (1 ml) at room temperature under argon.After 24 hr, the reaction mixture was partitioned between water (20 ml)and diethyl ether (30 ml). The layers were separated and the aqueouslayer was extracted with diethyl ether (2×30 ml). The combined organicextracts were dried over magnesium sulfate and evaporated in vacuo. Theresidue was purified by flash column chromatography (SiO₂, ethylacetate/petrol, 1:9 v/v) to give the title compound as a cream solid (23mg, 44%); m/z (ES⁺) 465 (M+H)⁺.

Intermediate 57trans-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylEthylcarbamate

N,N-Diisopropylethylamine (199 μl) and ethyl isocyanate (90 μl) wereadded to a stirred solution oftrans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (50mg) in dry dichloroethane (1 ml) at room temperature under argon. Thereaction mixture was heated to 40° C. for 120 h, and was partitionedbetween water (50 ml) and ethyl acetate (50 ml). The layers wereseparated and the aqueous layer was extracted with ethyl acetate (2×50ml). The combined organic extracts were dried over magnesium sulfate andevaporated in vacuo. The residue was purified by flash columnchromatography (SiO₂, ethyl acetate/petrol, 1:2 v/v) to give the titlecompound as a solid (55 mg, 95%); R_(f) (ethyl acetate/petrol, 1:2 v/v)0.65.

Intermediate 58trans-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylCyclohexylcarbamate

N,N-Diisopropylethylamine (199 μl) and cyclohexyl isocyanate (128 μl)were added to a stirred solution of4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (50 mg) indry dichloroethane (1 ml) at room temperature under argon. The reactionmixture was heated to 40° C. for 120 h, and was partitioned betweenwater (50 ml) and ethyl acetate (50 ml). The layers were separated andthe aqueous layer was extracted with ethyl acetate (2×50 ml). Thecombined organic extracts were dried over magnesium sulfate andevaporated in vacuo. The residue was purified by flash columnchromatography (SiO₂, ethyl acetate/petrol, 1:2 v/v) to give the titlecompound as a pale yellow solid (30 mg, 47%); δ_(H)(CDCl₃) 0.12 (6H, s),0.18 (6H, s), 0.90 (9H, s), 0.95 (9H, s). 1.00-2.10 (18H, m), 2.70-2.80(1H, m), 3.36-3.50 (1H, m), 4.40-4.48 (1H, m), 4.50-4.62 (1H, m), 6.20(1H, d), 6.32 (1H, dd), 6.86 (1H, d).

Intermediate 59 trans-4-(2,4-Dihydroxyphenyl)cyclohexanol

4-(2,4-Dihydroxyphenyl)cyclohexanone (18 mg) was placed in around-bottomed flask equipped with magnetic stirrer. Ethanol (5 ml) wasadded, followed by sodium borohydride (3.3 mg), and the reaction mixturewas stirred for 16 hr. Aqueous HCl (20 ml, 1M), followed by ethylacetate (20 ml), was added, and the organic phase removed and washedwith brine (15 ml), dried over anhydrous magnesium sulphate, filtered,and then concentrated in vacuo. The residue was purified by flash columnchromatography (SiO₂, ethyl acetate/petroleum ether, 60:40, v/v) toafford the title compound (14 mg, 78%) as a white solid. δ_(H)(CD₃OD)1.38-1.56 (4H, m), 1.85-1.88 (2H, m), 2.04-2.07 (2H, m), 2.80 (1H, tt),3.58-3.65 (1H, m), 6.24-6.29 (2H, m), 6.90 (1H, d); m/z (ES⁻) 267((M+AcOH)−1)

Intermediate 60cis-4-(2,4-Bis{[tert-Butyl(dimethyl)silyl]oxy}phenyl)cyclohexylMethanesulfonate

To a round bottom flask containingcis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexanol (200mg, 0.46 mmol) was added dichloromethane (10 ml) followed bytriethylamine (96 μl, 0.69 mmol) and dimethylaminopyridine (catalyticamount). The flask was purged with argon and methane sulfonyl chloride(53 μl, 0.69 mmol) was added with stirring. Stirring was continued for afurther 24 hr and the reaction mixture was poured into water andextracted with dichloromethane (4×20 ml). The combined organic extractswere washed with brine, dried over magnesium sulfate and concentrated invacuo. Purification via flash column chromatography (SiO₂, ethylacetate/petrol, 1:9) afforded the title compound as an oil (194 mg,82%). δ_(H)(CDCl₃) 0.19 (6H, s), 0.22 (6H, s), 0.97 (9H, s), 1.01 (9H,s), 1.20-1.35 (2H, m), 1.65-1.78 (4H, m), 2.15-2.22 (2H, m), 2.85-2.95(1H, m), 3.02 (3H, s), 5.06 (1H, s), 6.30 (1H, d), 6.43 (1H, dd), 7.00(1H, d).

Intermediate 61[4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]methylPropionate

4-Dimethylaminopyridine (catalytic amount), triethylamine (68 μl) andpropionyl chloride (42 μl) were added to a stirred solution of[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexyl]methanolin anhydrous dichloromethane (3 ml) at room temperature under argon.After 16 hr, the reaction mixture was partitioned between water (10 ml)and ethyl acetate (20 ml). The layers were separated and the aqueouslayer was extracted with ethyl acetate (2×20 ml). The combined organicextracts were dried over magnesium sulfate and evaporated in vacuo. Theresidue was purified by flash column chromatography (SiO₂, ethylacetate/petrol, 1:19 v/v) to give the title compound as a yellow oil anda mixture of diastereoisomers (114 mg, 92%); δ_(H)(CDCl₃) −0.04 (6H, s),0.02 (6H, s), 0.96 (9H, s), 1.00 (9H, s), 1.08-1.18 (3H, m), 1.20-2.10(9H, m), 2.24-2.40 (2H, m), 2.76-2.92 (1H, m), 3.94 (0.6H, d), 4.18(0.4H, d), 6.26 (1H, m), 6.40 (1H, dd), 6.94-6.98 (1H, m).

Intermediates 62 and 63 Diastereoisomers of Ethyl4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-hydroxycyclohexanecarboxylate

A round bottom flask equipped with stirrer bar was charged withtetrahydrofuran (6 ml), ethyl vinyl ether (0.28 ml, 2.92 mmol) andcooled to −78° C. A solution of tert-butyl lithium (1 ml, 1.7 M, 1.7mmol) was added dropwise and the flask allowed to reach 0° C. The flaskwas maintained at this temperature until the bright yellow colour hadbeen discharged before being re-cooled to −78° C. A solution of4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexanone (250 mg, 0.58mmol) in THF (4 ml) was added dropwise. After 30 min the reaction wasquenched with wet THF (0.5 ml water in 5 ml of THF), poured into water(10 ml) and extracted with diethyl ether (3×10 ml). The combined organicextracts were washed with brine, dried over magnesium sulfate andconcentrated in vacuo. This residue was dissolved in methanol (40 ml),cooled to −78° C. and ozonised oxygen passed through the solution for 10min. After this time the excess ozone was removed by passing oxygenthrough the solution. The reaction mixture was allowed to warm to roomtemperature and concentrated in vacuo. Purification via flash columnchromatography (SiO₂, ethyl acetate/petrol, 1:6) afforded the titlecompounds. First eluted diastereoisomer (31 mg, 11%); δ_(H)(CDCl₃) 0.18(6H, s), 0.25 (6H, s), 0.97 (9H, s), 1.02 (9H, s), 1.30 (3H, t),1.80-1.95 (8H, m), 2.82-2.95 (2H, m), 4.23 (2H, q), 6.28 (1H, d), 6.42(1H, dd), 7.05 (1H, d). Second eluted diastereoisomer (32 mg, 12%); 5H(CDCl₃) 0.20 (6H, s), 0.25 (6H, s), 0.95 (9H, s), 1.00 (9H, s), 1.36(3H, t), 1.62-1.85 (6H, m), 2.10-2.22 (2H, m), 2.87-2.98 (2H, m), 4.28(2H, q), 6.28 (1H, d), 6.42 (1H, dd), 6.97 (1H, d).

Intermediate 64 4-{2,4-Bis [tert-butyl(dimethyl)silyloxy]phenylCyclohexanone Oxime

To a round bottomed flask equipped with magnetic stirrer was added4-{2,4-bis [tert-butyl(dimethyl)silyloxy]phenyl cyclohexanone (100 mg,0.23 mmol) and ethanol (5 ml). To the stirred suspension was addedhydroxylamine hydrochloride (32 mg, 0.46 mmol) and triethylamine (103μl, 0.74 mmol), then the solution was heated under reflux temperaturefor 2.5 hr. The solution was allowed to cool to room temperature thenevaporated to dryness in vacuo. The residue was partitioned betweenethyl acetate (20 ml) and water (10 ml) and the layers separated. Theaqueous layer was extracted with ethyl acetate (3×20 ml) and thecombined organic layers washed with brine (10 ml), dried over magnesiumsulfate, filtered and concentrated in vacuo. The title compound wasisolated (103 mg, 100%) as a white. δ_(H)(CDCl₃) 0.19 (6H, s), 0.24 (6H,s), 0.95 (9H, s), 1.02 (9H, s), 1.43-1.62 (2H, m), 1.77-1.87 (1H, m),1.93-2.04 (2H, m), 2.18-2.24 (1H, m), 2.46-2.53 (1H, m), 3.05-3.15 (1H,m), 3.41-3.50 (1H, m), 6.30 (1H, d), 6.40 (1H, dd), 6.79 (1H, br), 6.92(1H, d).

Example 1 4-(2,4-Dihydroxyphenyl)-3-cyclohexen-1-one

A round bottomed flask equipped with magnetic stirrer was charged with8-[2,4-bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]dec-7-ene (1.50 g,4.24 mmol) and methanol (30 ml). To the stirred solution was addedaqueous hydrochloric acid (30 ml, 1.0M) and the solution was heated toreflux temperature for 1.5 hr. After cooling to room temperature,saturated aqueous sodium bicarbonate (20 ml) was added and the layersseparated. The aqueous layer was extracted with ethyl acetate (4×20 ml)and the combined organic layers washed with brine (20 ml), dried overmagnesium sulfate, filtered and concentrated in vacuo. The resulting oilwas purified via flash column chromatography (SiO₂, ethylacetate/petroleum ether, 1:3, v/v) to afford the title compound as ayellow solid (323 mg, 37%). m/z (ES⁻) 203 (M−H⁺); δ_(H)(CD₃OD) 2.62 (2H,t), 2.86 (2H, t), 3.04 (2H, m), 5.78 (1H, m), 6.28 (1H, m), 6.32 (1H,m), 6.96 (1H, d).

Example 2a 4-(2,4-Dihydroxyphenyl)cyclohexanone

A round bottomed flask equipped with magnetic stirrer was loaded8-[2,4-bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]decane (1.30 g, 3.9mmol) and methanol (15 ml). To the resulting stirred solution was addedaqueous HCl (15 ml, 1M) in one portion. After stirring for one hr atroom temperature the acid was quenched by adding saturated aqueoussodium bicarbonate solution (10 ml). After stirring vigorously for 10min, the reaction mixture was transferred to a separating funnel and thephases separated and the aqueous phase was extracted with ethyl acetate(3×20 ml). The combined organic phases were washed with brine and thesolvent evaporated. To the slightly wet crude product was added methanol(30 ml) and acidic ion exchange resin (4 g). The resulting mixture washeated under reflux, with stirring, for 5 hr. Filtering through a plugof Celite, washing with ethyl acetate, followed by removal of solvent invacuo afforded an orange oil. Purification by flash columnchromatography, (SiO₂, ethyl acetate/petroleum ether, 1:1, v/v)furnished the title compound as a white powder (0.54 g, 68%). m/z (ES⁻)411 (2M−1); δ_(H)(CD₃OD) 1.94 (2H, ddd), 2.16-2.23 (2H, m), 2.41 (2H,dt), 2.62 (1H, t), 2.63 (1H, t), 6.24 (1H, dd), 6.31 (1H, d), 6.92 (1H,d).

Example 2b 4-(2,4-Dihydroxyphenyl)cyclohexanone

A round bottomed flask equipped with magnetic stirrer was charged with4-(1,4-dioxaspiro[4.5]dec-8-yl)-1,3-benzenediol (11.3 g, 45.2 mmol),acetone (250 ml) and water (50 ml). To the stirred solution was addedpyridinium p-toluenesulfonate (1.14 g, 4.52 mmol) in one portion and thereaction mixture was then heated to reflux temperature for 8 hr. Afterallowing the reaction mixture to cool to room temperature, most of theacetone was removed in vacuo and the remaining mixture was partitionedbetween ethyl acetate (200 ml) and water (50 ml). The aqueous layer wasextracted with ethyl acetate (3×50 ml) and the combined organic layerswere washed with brine (30 ml), dried over magnesium sulfate, filteredand concentrated under reduced pressure to afford an off white powder.After washing the powder with dichloromethane (100 ml) and removal ofexcess solvent under reduced pressure, the desired product (9.30 g,100%) was obtained as an off-white white powder. m/z (ES⁺) 207 (M+H⁺);δ_(H)(CD₃OD) 1.84-1.97 (2H, m), 2.15-2.23 (2H, m), 2.36-2.45 (2H, m),2.58-2.68 (2H, m), 3.39 (1H, tt), 6.26 (1H, dd), 6.34 (1H, d), 6.96 (1H,d).

Example 3 4-(2,4-Dihydroxyphenyl)cyclohexanone Oxime

To a round bottomed flask, equipped with magnetic stirrer was added4-(2,4-dihydroxyphenyl)cyclohexanone (100 mg, 0.49 mmol), anhydrousethanol (5 ml), triethylamine (102 ml) and hydroxylamine hydrochloride(51 mg, 0.73 mmol). The reaction mixture was heated under reflux for 3hr, then evaporated in vacuo. The resulting solid was purified by flashcolumn chromatography, (SiO₂, ethyl acetate/petroleum ether, 35:65,v/v), furnishing the title compound as short white needles (107 mg,100%). δ_(H)(CD₃OD) 1.44-1.61 (2H, m), 1.81-1.88 (1H, m), 1.94-2.00 (2H,m), 2.19-2.27 (1H, m), 2.43 (1H, d), 3.04-3.10 (1H, m), 3.38 (1H, m),6.22-6.25 (1H, m), 6.28 (1H, d), 6.84-6.86 (1H, m); m/z (EI⁻) 220.

Example 4 O-Methyl-4-(2,4-dihydroxyphenyl)cyclohexanone Oxime

To a round bottomed flask, equipped with magnetic stirrer was added4-(2,4-dihydroxyphenyl)cyclohexanone (21 mg, 0.10 mmol), anhydrousethanol (3 ml), sodium acetate (16 mg, 0.20 mmol) andO-methylhydroxylamine hydrochloride (9 mg, 0.22 mmol). The reactionmixture was heated under reflux for 6 hr, then partitioned between ethylacetate (10 ml) and water (10 ml). The organic layer was dried overanhydrous calcium sulphate, filtered and evaporated in vacuo furnishinga colourless oil. Purification via flash column chromatography (SiO₂,ethyl acetate/petroleum ether, 1:1, v/v), afforded the title compound asa white solid (11 mg, 47%). δ_(H)(CD₃OD) 1.43-1.63 (2H, m), 1.81-1.92(2H, m), 1.93-2.20 (2H, m), 2.24 (1H, dt), 2.38-2.44 (1H, m), 3.07 (1H,tt), 3.78 (3H, s), 6.20-6.23 (1H, m), 6.26 (1H, d), 6.85 (1H, d); m/z(ES⁻) 234.

Example 5 O-Benzyl-4-(2,4-dihydroxyphenyl)cyclohexanone Oxime

To a round bottomed flask, equipped with magnetic stirrer, was added4-(2,4-dihydroxyphenyl)cyclohexanone (21 mg, 0.10 mmol), anhydrousethanol (3 ml), sodium acetate (17 mg, 0.21 mmol) andO-benzylhydroxylamine hydrochloride (18 mg, 0.21 mmol). The reactionmixture was heated under reflux for 6 hr, then partitioned between ethylacetate (10 ml) and water (10 ml). The organic layer was dried overanhydrous calcium sulphate, filtered and evaporated in vacuo furnishinga pale pink oil which was purified by flash column chromatography (SiO₂,ethyl acetate/petroleum ether, 1:1, v/v) to afford the title compound asa colourless oil (11 mg, 32%). δ_(H) (400, CDCl₃) 1.47-1.68 (2H, m),1.86-1.95 (1H, m), 1.97-2.08 (2H, m), 2.25 (1H, dt), 2.49-2.57 (1H, m),3.02 (1H, tt), 3.42-3.50 (1H, m), 4.78 (1H, s), 4.89 (1H, s), 6.25-6.29(1H, m), 6.33-6.37 (1H, m), 6.94 (1H, d), 7.26-7.39 (5H, m); m/z (ES⁻)310.

Example 6 3-(2,4-dihydroxyphenyl)-2-cyclohexen-1-one

3-[2,4-Bis(methoxymethoxy)phenyl]-2-cyclohexen-1-one (50 m g) was heatedto 50° C. in methanol (4 ml) containing acidic ion exchange resin (500mg). After 2 hr, the mixture was filtered and the filtrate wasevaporated in vacuo and purified by flash column chromatography (SiO₂,ether/petroleum ether, 9:1, v/v) to furnish the title compound as ayellow solid (31 mg, 76%). δ_(H) (DMSO) 1.95 (2H, quintet), 2.30 (2H,t), 2.69 (2H, t), 6.26 (2H, overlapping m), 6.35 (1H, m), 7.10 (1H, d),9.67 (1H, bs), 9.86 (1H, bs); m/z (ES⁻) 407 (2M−H)⁻.

Example 7 (±)-3-(2,4-Dihydroxyphenyl)cyclohexanone

(±)-3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexanone (35 mg) in methanol(4 ml) containing acidic ion exchange resin (300 mg) was stirred at 50°C. for 6 hr, and then at ambient temperature for 16 hr. The mixture wasevaporated in vacuo and the residue was redissolved in acetone (4 ml)containing water (2 drops) and stirred at 50° C. for 8 hr, then atambient temperature for 64 hr. The mixture was filtered through celiteand purified by flash column chromatography (SiO₂, petroleum ether/ethylacetate 1:1 v/v) to furnish the title compound as a white solidcontaining an equilibrium mixture of cyclized and uncyclized forms (31mg, 76%). δ_(H) (DMSO) 1.1-2.3 (8H, overlapping m), 3.0 (1H, m), 6.08(0.5H, bs), 6.16 (1H, bd), 6.25 (0.5H, bs), 6.53 (0.5H, bs), 6.75 (0.5H,d), 6.89 (0.5H, b), 8.98 (0.5H, bs), 9.02 (0.5H, bs), 9.17 (0.5H, bs);m/z (ES⁻) 205 (M−H)⁻.

Example 8 3-(2,4-Dihydroxyphenyl)-2-cyclohexen-1-one Oxime

3-[2,4-Bis(methoxymethoxy)phenyl]-2-cyclohexen-1-one oxime (0.1 g) washeated to 50° C. in methanol (5 ml) containing acidic ion exchange resin(0.3 g). After 4 hr, the mixture was filtered and the resin was washedwith ammonia solution (50 ml). Filtrate and washings were combined,evaporated in vacuo and purified by flash column chromatography (SiO₂,ethyl acetate/petroleum ether, 3:2, v/v) to furnish the title compoundas a yellow solid (0.058 g, 81%). δ_(H) (DMSO) (mixture ofstereoisomers) 1.68 (2H, m, major), 1.76 (2H, m, minor), 2.26 (2H, m,minor), 2.40-2.54 (4H major+2H minor, overlapping m), 6.15-6.30 (3Hmajor+2H minor, overlapping m), 6.85-6.95 (1H major+2H minor,overlapping m), 9.26 (1H, bs, major), 9.32 (1H, bs, minor), 9.35 (1H,bs, major), 9.40 (1H, bs, minor), 10.17 (1H, s, minor), 10.49(1H, s,major); m/z (ES⁻) 437 (2M−H)⁻.

Example 9 (±)-3-(2,4-Dihydroxyphenyl)cyclohexanone Oxime

(±)-3-(2,4-Dihydroxyphenyl)cyclohexanone (13 mg), hydroxylaminehydrochloride (0.0065 g), and triethylamine (16 μl) were heated at 80°C. in DMF (3 ml). After 3 hr, the reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed withbrine, dried over magnesium sulfate, and evaporated in vacuo. Theresidue was purified by flash column chromatography (SiO₂, petroleumether/ethyl acetate 3:2 v/v) to furnish the title compound as a whitesolid (12 mg, 86%). δ_(H)(CD₃OD) 1.4-2.0 (6H, overlapping m), 2.10(0.5H, m), 2.20 (0.5H, m), 2.35 (0.5H, m), 2.46 (0.5H, m), 2.94 (1H, m),6.22-6.26 (2H, overlapping m), 6.92-6.95 (1H, overlapping m); m/z (ES⁺)222 (M+H)⁻.

Example 10 (±)-4-[3-(1-Piperazinyl)cyclohexyl]-1,3-benzenediolTrifluoroacetic Acid Salt

(±)-1-{3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexyl}piperazine (35 mg)was heated under reflux in methanol containing acidic ion exchange resin(0.3 g) for 5 hr. The reaction mixture was filtered, and the resin waswashed with methanol and aqueous ammonia, and the combined filtrate andwashings were concentrated in vacuo. The crude residue was purified bypreparative HPLC to furnish the title compound as an off white solid (14mg, 38%). δ_(H) (d₄-MeOH) 1.7-1.9 (6H, overlapping m), 2.05 (1H, m),2.20 (1H, m), 3.1-3.5 (10H, overlapping m), 6.26 (2H, overlapping m),6.94 (1H, d); m/z (ES⁺) 277 (M+H)⁺.

Example 11 (±)-N-[3-(2,4-Dihydroxyphenyl)cyclohexyl]methanesulfonamide

(±)-N-{3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexyl}methanesulfonamide(34 mg) was heated under reflux in methanol (2 ml) containing acidic ionexchange resin (0.3 g) for 5 hr. The reaction mixture was filtered andthe resin was washed with methanol. The combined filtrate and washingswere evaporated in vacuo and the crude residue was purified bypreparative HPLC to furnish a mixture of diastereoisomers of the titlecompound as a pale pink solid (10 mg, 38%). δ_(H) (d₄-MeOH) 1.20-2.00(7H, overlapping m), 2.07 (1H, m), 2.90 (0.5H, m), 2.93 (1.5H, s), 2.97(1.5H, s), 3.13 (0.5H, m), 3.30 (0.5H, m), 3.80(0.5H, m), 6.21-6.26 (1H,dd), 6.87 (0.5H, d), 6.89 (0.5H, d); m/z (ES⁻) 284 (M−H)⁻.

Example 12 (±)-4-[3-(Hydroxymethyl)cyclohexyl]-1,3-benzenediol

(±)-{3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexyl}methanol (35 mg) washeated at 50° C. in methanol (3.5 ml) containing acidic ion exchangeresin (350 mg). After 6 hr, the mixture was filtered, the resin waswashed with ethyl acetate, and the combined filtrate and washings wereevaporated in vacuo. The crude residue was purified by flash columnchromatography (SiO₂, ethyl acetate/petrol, 1:1 v/v) to furnish amixture of diastereoisomers of the title compound as a white solid (2mg, 8%). δ_(H) (d₄-MeOH) 0.9-1.9 (9H, overlapping m), 2.80 (0.5H, m),2.90 (0.5H, m), 3.20-3.40 (2H, overlapping m), 6.15 (2H, m), 6.80 (0.5H,d), 6.85 (0.5H, d); m/z (ES⁻) 221 (M−H)⁻.

Example 13 (±)-4-[3-(Hydroxyamino)cyclohexyl]-1,3-benzenediolTrifluoroacetate Salt

Cis-N-{3-[2,4-bis(methoxymethoxy)phenyl]cyclohexyl}hydroxylamine (0.015g) was heated under reflux in methanol (2 ml) containing acidic ionexchange resin (0.3 g) for 5 hr. The reaction mixture was filtered, andthe resin was washed with aqueous ammonia and methanol and the combinedfiltrate and washings were concentrated in vacuo. The crude residue waspurified by preparative HPLC to furnish the title compound as an offwhite solid (0.005 g, 46%). δ_(H) (d₄-MeOH) 1.25-1.60 (4H, overlappingm), 1.82 (1H, bd), 2.02 (1H, m), 2.17 (2H, overlapping m), 2.93 (1H, m),3.36 (1H, m) 6.24 (1H, dd), 6.27 (1H, d), 6.88 (1H, d); m/z (ES⁺) 224(M+H)⁺.

Example 14 4-(4-Methylenecyclohexyl)-1,3-benzenediol

Tetrabutylammonium fluoride (230 μl) was added to a stirred solution oftert-butyl-[3-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-methylenecyclohexyl)phenoxy](isopropyl)dimethylsilane(40 mg) in tetrahydrofuran (2 ml) at room temperature. After 24 hr,further tetrabutylammonium fluoride (50 μl) was added, and after 2 hrthe solvent was removed under reduced pressure. The residue waspartitioned between water (20 ml) and ethyl acetate (20 ml). The layerswere separated and the aqueous layer was extracted with ethyl acetate(2×20 ml). The combined organic extracts were washed with brine, driedover magnesium sulfate and evaporated in vacuo. The residue was purifiedby flash column chromatography (SiO₂, ethyl acetate/petrol, 2:3 v/v) togive the title compound as a white solid (17 mg, 90%). δ_(H)(CD₃OD)1.25-1.40 (2H, m), 1.75-1.82 (2H, m), 2.04-2.15 (2H, m), 2.22-2.30 (2H,m), 2.86 (1H, tt), 3.20 (1H, m), 4.50 (2H, s), 6.10-6.16 (2H, m), 6.72(1H, d); m/z (ES⁺) 205 (M+H)⁺.

Example 15 cis/trans-4-[4-(Hydroxymethyl)cyclohexyl]-1,3-benzenediol

cis/trans-[4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]methanol(24 mg) was dissolved in THF (5 ml), and tetrabutylammonium fluoride(0.12 ml, 1.0M in THF) was added. The resulting solution was stirred atroom temperature for 15 hr and then partitioned between ethyl acetate(20 ml) and water (2 ml). The aqueous phase was extracted with ethylacetate (3×20 ml) and the combined organic phases were washed with brine(20 ml), dried over anhydrous magnesium sulphate, and concentrated invacuo. Purification via flash column chromatography (SiO₂ eluting withethyl acetate:petroleum ether, 1:1 v/v) furnished the desired compound(7 mg, 59%) as a white solid. δ_(H)(CD₃OD): 0.95-1.06 (0.5H, m),1.24-1.38 (0.5H, m), 1.43-1.60 (4H, m), 1.69-1.83 (4H, m), 2.62-2.77(1H, m), 3.30 (1H, d), 3.56 (1H, d), 6.11-6.17 (2H, m), 6.76-7.01 (1H,m); m/z (ES⁻) 281 (M−1+60)⁻.

Example 16 cis/trans-4-(4-Hydroxy-4-methylcyclohexyl)-1,3-benzenediol

cis/trans-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methylcyclohexanol(29 mg) was dissolved in THF (8 ml), and tetrabutylammonium fluoride(0.14 ml, 1.0M in THF) was added in one portion with stirring. Theresulting solution was stirred for 17 hr and then partitioned betweenethyl acetate (30 ml) and water (5 ml). The aqueous phase was extractedwith ethyl acetate (2×10 ml), and the combined organic phases washedwith brine (20 ml), dried over anhydrous magnesium sulphate, andconcentrated in vacuo. Purification via flash column chromatography(SiO₂ eluting with ethyl acetate:petroleum ether, 1:19 v/v graduallyincreasing polarity to 3:7 v/v) afforded the title product as theindividual 1,4-cis (5 mg, 36%) and 1,4-trans (9 mg, 64%)diastereoisomers (white solids). Cis isomer: δ_(H)(CD₃OD): 1.30 (3H, s),1.50-1.66 (4H, m), 1.69-1.77 (4H, m), 2.74-2.82 (1H, m), 6.20-6.26 (2H,m), 6.89 (1H, d); m/z (ES⁻) 281 (M−1+60). Trans isomer: δ_(H) (CD₃OD):1.22 (3H, s), 1.46-1.60 (4H, m), 1.69-1.82 (4H, m), 2.75 (1H, tt),6.22-6.26 (2H, m), 6.93 (1H, d); m/z (ES⁻) 281 (M−1+60).

Example 17 cis/trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]acetamide

To a round bottomed flask equipped with magnetic stirrer was addedcis/trans-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]acetamide (15 mg, 31 μmol), tetrahydrofuran (3 ml) andtetra-n-butylammonium fluoride (93 μl, 93 μmol, 1.0M solution intetrahydrofuran). The resulting solution was stirred for 3 hr.Tetra-n-butylammonium fluoride (90 μl, 90 μmol, 1.0M solution intetrahydrofuran) was added and the solution stirred for a further 64 hr.Saturated aqueous sodium bicarbonate solution (3 ml) was added and thesolvents removed in vacuo. The residue was partitioned between ethylacetate (20 ml) and water (5 ml) and the aqueous layer extracted withethyl acetate (3×10 ml). The combined organic layers were washed withbrine (10 ml), dried over magnesium sulfate, filtered and concentratedin vacuo. Purification via flash column chromatography (SiO₂,methanol/dichloromethane, 1:9, v/v) afforded an oily solid (6 mg) whichwas a mixture of isomers by NMR. Further purification via HPLC affordedthe title compound (0.5 mg, 6%) as a mixture of diastereoisomers and acolourless oil. m/z (ES⁻) 308 (M−1+60{acetate}); δ_(H)(CD₃OD) 1.41 (1H,m), 1.57 (1H, m), 1.70 (2H, m), 1.83 (1H, m), 1.87 (1H, m), 1.93 (1H,m), 1.96 (1.5H, m), 2.04 (1.5H, m), 2.05 (1H, m), 2.82 (1H, m), 3.72(0.5H, m), 4.14 (0.5H, m), 6.28 (2H, m), 6.92 (0.5H, dd), 6.97 (0.5H,dd).

Example 18 (±)-O-Methyl-3-(2,4-dihydroxyphenyl)cyclohexanone Oxime

(±)-3-(2,4-Dihydroxyphenyl)cyclohexanone (22 mg), methoxylaminehydrochloride (18 mg) and sodium acetate (18 mg) were heated underreflux in ethanol. After 6 hr, further methoxylamine (36 mg) and sodiumacetate (36 mg) were added and the mixture heated under reflux for afurther 1 hr. The reaction mixture was evaporated in vacuo and theresidue was partitioned between ethyl acetate (20 ml) and water (20 ml).The aqueous layer was extracted with ethyl acetate (2×20 ml), and thecombined organic extracts were dried over magnesium sulfate andevaporated in vacuo. The crude residue was purified by flash columnchromatography (SiO₂, ethyl acetate/petrol, 1:1 v/v) to furnish thetitle compound as a mixture of isomers (18 mg, 72%). δ_(H)(CDCl₃)1.5-2.2 (6H, overlapping m), 2.42 (0.5H, bd), 2.69 (0.5H, bd), 2.92(0.5H, m), 3.06 (0.5H, m), 3.24-3.38 (1H, m), 3.81 (1.5H, s), 3.88(1.5H, s), 5.42 (0.5H, bs), 5.47 (0.5H, bs), 6.28-6.42 (2H, overlappingm), 6.86 (0.5H, bs), 6.98 (1H, m), 7.06 (0.5H, bs); m/z (ES−) 469(2M−1)⁻.

Example 19 (±)-3-(2,4-Dihydroxyphenyl)-1-methylcyclohexanol

Methyl magnesium chloride (0.132 ml of a 22% w/w solution intetrahydrofuran) was added to a solution of(±)-3-(2,4-dihydroxyphenyl)cyclohexanone (20 mg) in tetrahydrofuran (3ml) at 0° C. under argon. After 16 hr, dilute hydrochloric acid (1 ml)was added dropwise and the reaction mixture was partitioned betweenethyl acetate (50 ml) and brine (50 ml). The aqueous layer was extractedwith ethyl acetate (2×50 ml), and the combined organic extracts weredried over magnesium sulfate and evaporated in vacuo. The crude residuewas purified by preparative HPLC to furnish the title compound as awhite solid (6 mg, 28%). δ_(H) (d₄-MeOH) 1.20 (3H, s), 1.22-1.39 (2H,overlapping m), 1.46 (1H, t), 1.54-1.87 (5H, overlapping m), 3.22 (1H,m), 6.19-6.25 (2H, overlapping m), 6.86 91H, d); m/z (ES⁻) 281(M+60−H)⁻.

Example 20 (±)-O-Benzyl-3-(2,4-dihydroxyphenyl)cyclohexanone Oxime

(±)-3-(2,4-Dihydroxyphenyl)cyclohexanone (30 mg), O-benzylhydroxylaminehydrochloride (46 mg) and sodium acetate (24 mg) were heated underreflux in ethanol (3 ml). After 16 hr, the reaction mixture wasevaporated in vacuo and the residue was partitioned between ethylacetate (50 ml) and brine (50 ml). The aqueous layer was extracted withethyl acetate (2×50 ml), and the combined organic extracts were driedover magnesium sulfate and evaporated in vacuo. The crude residue waspurified by preparative HPLC to furnish a mixture of geometric isomersof the title compound as an off white solid (12 mg, 26%). δ_(H)(d₄-MeOH) 1.42-2.06 (6H, overlapping m), 2.12 (0.5H, dt), 2.22 (0.5H,t), 2.34 (0.5H, m), 2.46 (0.5H, m), 2.96 (1H, m), 5.02 (2H, s),6.20-6.27 (2H, overlapping m), 6.92 (1H, m), 7.22-7.34 (5H, overlappingm); m/z (ES⁻) 310 (M−H)⁻.

Example 21 3-(2,4-Dihydroxyphenyl)-2-cyclopentenone Oxime

3-[2,4-Bis(methoxymethoxy)phenyl]-2-cyclopenten-1-one (20 mg) was heatedat 50° C. in MeOH (4 ml) containing acidic ion exchange resin (100 mg)for 3 hr. The reaction mixture was filtered and the resin washed withethyl acetate (20 ml). The filtrate was concentrated in vacuo and theresidue purified by flash column chromatography (SiO₂, ethylacetate/petrol, 7:3 v/v) to furnish3-(2,4-dihydroxyphenyl)-2-cyclopenten-1-one (11 mg, 79%).3-(2,4-Dihydroxyphenyl)-2-cyclopenten-1-one (6 mg), hydroxylaminehydrochloride (3.3 mg) and triethylamine (6.6 μl) were heated in ethanol(3 ml) under reflux for 3 hr. The reaction mixture was partitionedbetween ethyl acetate (20 ml) and water (20 ml). The aqueous phase wasextracted with ethyl acetate (10 ml), and the combined organic phaseswere washed with brine (10 ml), dried over magnesium sulfate, andconcentrated in vacuo. The crude residue was purified by flash columnchromatography (SiO₂, ethyl acetate/petrol, 1:1 v/v) to furnish thetitle compound as a yellow solid and as one major isomer (4 mg, 62%).Data reported for the major isomer: δ_(H) (d⁴-MeOH) 2.74-2.77 (2H, m),2.96-2.99 (2H, m), 6.34 (1H, dd), 6.38 (1H, d), 6.96 (1H, t), 7.22 (1H,d); m/z (ES⁻) 204 (M−H)⁻.

Example 22 (±)-3-(2,4-Dihydroxyphenyl)cyclopentanone

(±)-3-[2,4-Bis(methoxymethoxy)phenyl]cyclopentanone (8 mg) was heated at50° C. in MeOH (3 ml) containing acidic ion exchange resin (0.1 g) for 3hr. The reaction mixture was filtered and the resin washed with ethylacetate (20 ml). The filtrate was concentrated in vacuo and the residuepurified by flash column chromatography (SiO₂, ethyl acetate) to furnishthe title compound as a white solid (3.8 mg, 70%). δ_(H) (d⁴-MeOH)2.52-2.13 (1H, m), 2.26-2.48 (4H, overlapping m), 2.53-2.60 (1H, m),3.55-3.61 (1H, m), 6.29 (1H, dd), 6.33 (1H, d), 6.96 (1H, d); m/z (ES⁻)251 ((M+60)−1)⁻.

Example 23 (±)-3-(2,4-Dihydroxyphenyl)cyclopentanone Oxime

(±)-3-(2,4-Dihydroxyphenyl)cyclopentanone (5 mg), hydroxylaminehydrochloride (2.7 mg) and triethylamine (5.4 uM) were heated in EtOH (4ml) under reflux for 3 hr. The reaction mixture was partitioned betweenethyl acetate (20 ml) and water (20 ml). The aqueous phase was extractedwith ethyl acetate (10 ml), and the combined organic phases were washedwith brine (10 ml), dried over magnesium sulfate, and concentrated invacuo. The crude residue was purified by flash column chromatography(SiO₂, ethyl acetate/petrol, 4:1 v/v) to furnish the title compound as awhite solid and a mixture of isomers (3.8 mg, 71%). δ_(H) (d⁴-MeOH)1.80-1.93 (1H, overlapping m), 2.05-2.20 (0.5H, m), 2.39-2.55 (3H,overlapping m), 2.68-2.74 (1H, overlapping m), 2.94 (0.5H, br dd),6.26-6.33 (2H, overlapping m), 6.94 (0.5H, d), 6.96 (0.5H, d); m/z (ES⁻)266 ((M+60)−1)⁻.

Example 24 cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-1-butanesulfonamide

To a round bottomed flask equipped with magnetic stirrer charged withcis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine(150 mg, 0.34 mmol) and 1,2-dichloroethane (8 ml), was addedtriethylamine (96 μl, 0.70 mmol) and n-butylsulfonyl chloride (55 μl,0.40 mmol) at room temperature. 4-Dimethylaminopyridine (3 crystals) wasadded and the mixture stirred for 17 hr. Aqueous sodium hydroxidesolution (15 ml, 0.40M) was added and the mixture stirred for 10 min.The layers were partitioned and the aqueous layer was extracted withdichloromethane (15 ml). The combined organic layers were washed withbrine (15 ml), dried over magnesium sulfate, filtered and concentratedin vacuo. The resulting solid was then dissolved in tetrahydrofuran (10ml) and acetic acid (0.15 ml), then tetra-n-butylammonium fluoridehydrate (360 mg, 1.4 mmol) was added. The mixture was stirred at roomtemperature for 1 hr, then ethyl acetate (10 ml) and water (15 ml) wereadded. The layers were partitioned and the aqueous layer was extractedwith ethyl acetate (10 ml). The combined organic layers were washed withbrine (10 ml), dried over magnesium sulfate, filtered and concentratedin vacuo to leave an oil. Purification via flash column chromatography(SiO₂, ethyl acetate/petroleum ether, 1:10 then 1:1, v/v) furnished thetitle compound (40 mg, 35%) as a white solid. m/z (ES⁻) 326 (M−H⁺);δ_(H)(CD₃OD) 0.95 (3H, t), 1.45-1.55 (2H, m), 1.55-1.95 (10H, m),2.80-2.90 (1H, m), 3.00-3.20 (2H, m), 3.65 (1H, m), 6.22-6.26 (2H, m),6.96 (1H, d).

Example 25 trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]methanesulfonamide

To a round bottomed flask equipped with magnetic stirrer was addedtrans-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]methanesulfonamide (320 mg, 0.57 mmol) and 1,2-dichloroethane (50 ml).To the stirred solution was added trifluoroacetic acid (20 ml) and water(20 ml). The stirred reaction mixture was then heated under reflux for18 hr and then cooled to room temperature. Toluene (70 ml) was added andthe solvent removed in vacuo. Methanol (50 ml) was then added to theresidue and the solvent removed under reduced pressure. The resultingoil was purified via flash column chromatography (SiO₂, ethylacetate/petroleum ether, 1:3, 1:2, then 1:1 v/v) to furnish the titleproduct (115 mg, 71%) as a white solid. m/z (ES⁺) 286 (M+H⁺);δ_(H)(CD₃OD) 1.52 (4H, m), 1.89 (2H, m), 2.13 (2H, m), 2.80 (1H, m),3.00 (3H, s), 3.28 (1H, m), 6.27 (1H, d), 6.29 (1H, dd), 6.92 (1H, d).

Example 26 cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]methanesulfonamide

To a round bottomed flask equipped with magnetic stirrer was addedcis-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]methanesulfonamide(44 mg, 100 μmol) and 1,2-dichloroethane (4 ml). To the stirred solutionwas added methanesulfonyl chloride (10 μl, 120 mmol), triethylamine (28μl, 200 μmol) and three crystals of 4-dimethylaminopyridine. Thereaction mixture was then left stirring for 17 hr. The reaction mixturewas then partitioned between aqueous sodium hydroxide (5 ml, 0.2M), anddichloromethane (5 ml). The aqueous phase was extracted withdichloromethane (2×5 ml) and the combined organic phases were washedwith brine (7 ml), dried over magnesium sulfate, filtered andconcentrated in vacuo to give a gum. This gum was dissolved indichloromethane (6 ml), then water (3 ml) and trifluoroacetic acid (3ml) were added and the mixture left to stir for 17 hr. The reactionmixture was diluted with toluene (15 ml) and the solvents were removedin vacuo. More toluene (15 ml) was added and evaporated under reducedpressure. Azeotropic removal of residual trifluoroacetic acid waseffected with methanol to give a gum (38 mg). The residue was dissolvedin dichloromethane (4.5 ml) and methanol (4.5 ml), then water (3 ml) andtrifluoroacetic acid (3 ml) were added. The reaction mixture was stirredat room temperature for 64 hr. The reaction mixture was diluted withtoluene (15 ml) and the solvents were removed in vacuo. More toluene (15ml) was added and evaporated under reduced pressure. Azeotropic removalof residual trifluoroacetic acid was effected with methanol to give anoil (28 mg) which was purified via flash column chromatography (SiO₂,ethyl acetate/petroleum ether, gradient elution using 1:3, 1:2, then 1:1v/v) to afford the title compound (13 mg, 81%) as a white solid. m/z(ES⁺) 286 (M+H⁺); δ_(H)(CD₃OD) 1.71 (6H, m), 1.90 (2H, m), 2.87 (1H, m),3.00 (3H, s), 3.72 (1H, m), 6.28 (1H, d), 6.30 (1H, dd), 7.01 (1H, d).

Example 27 4-[4-(4-Hydroxyphenyl)cyclohexyl]-1,3-benzenediol

To a round bottomed flask equipped with magnetic stirrer was addedtert-butyl(4-{4-[2,4-bis(methoxymethoxy)phenyl]cyclohexyl}phenoxy)dimethylsilane(118 mg, 0.24 mmol), methanol (10 ml) and acidic Dowex® resin (500 mg).The reaction mixture was heated to reflux temperature for 5 hr thencooled to room temperature and filtered through a celite plug, washingwith ethyl acetate. The filtrate was adsorbed onto silica gel andpurified via flash column chromatography (SiO₂, ethyl acetate/petroleumether, 2:3, v/v) to afford a white solid (44 mg) which was purifiedfurther by HPLC. The title compound was isolated as a white solid (12mg, 17%). m/z (ES⁻) 283 (M−H⁺); δ_(H)(CD₃OD) 1.52-1.96 (6H, m), 2.11(2H, m), 2.53 and 3.07 (1H, m), 2.90 (1H, m), 6.28 (2H, m), 6.75 (2H,m), 6.95 (1H, m), 7.10 (1H, m), 7.19 (1H, m).

Example 28 cis/trans-Methyl [4-(2,4-dihydroxyphenyl)cyclohexyl]acetate

To a round bottomed flask equipped with magnetic stirrer was addedcis/trans-methyl {4-[2,4-bis(methoxymethoxy)phenyl]cyclohexyl} acetate(1.00 g, 2.84 mmol) and methanol (20 ml). The stirred solution washeated to reflux temperature and aqueous hydrochloric acid (20 ml, 1 M)was added in aliquots (4×5 ml) at 10 min intervals. After 2 hr, thereaction mixture was cooled to room temperature and saturated aqueoussodium bicarbonate (50 ml) added. The reaction mixture was poured into aseparating funnel containing ethyl acetate (100 ml) and water (30 ml).The layers were separated and the aqueous layer was extracted with ethylacetate (3×30 ml). The combined organic layers were washed with brine(20 ml), dried over magnesium sulfate, filtered and concentrated invacuo to give a white solid. Purification via flash columnchromatography (SiO₂, ethyl acetate/petroleum ether, 1:2, v/v) affordedthe title compound (0.51 g, 69%) as a mixture of diastereoisomers. m/z(ES⁺) 265 (M+H⁺); δ_(H)(CD₃OD) 1.33-1.91 (9H, m), 2.30 (2H, m), 2.79(1H, m), 3.72 (3H, s), 6.28 (2H, m), 6.95 (1H, m).

Example 29 trans-Methyl [4-(2,4-dihydroxyphenyl)cyclohexyl]acetate

cis/trans-Methyl [4-(2,4-dihydroxyphenyl)cyclohexyl]acetate (25 mg) waspurified via HPLC (acetonitrile/water, 30:70-80:20, 20 min isocratic) toafford the title compound as a white solid. m/z(ES⁺) 265 (M+H⁺);δ_(H)(CD₃OD) 1.21 (2H, m), 1.47 (2H, m), 1.64 (1H, m), 1.88 (4H, m),2.29 (2H, d), 2.79 (1H, m), 3.70 (3H, s), 6.28 (2H, m), 6.92 (1H, d).

Example 30 cis-Methyl [4-(2,4-dihydroxyphenyl)cyclohexyl]acetate

cis/trans-Methyl [4-(2,4-dihydroxyphenyl)cyclohexyl]acetate (25 mg) waspurified via HPLC (acetonitrile/water, 30:70-80:20, 20 min isocratic) toafford the title compound as a white solid. m/z(ES⁺) 265 (M+H⁺);δ_(H)(CD₃OD) 1.60-1.79 (8H, m), 2.31 (1H, m), 2.54 (2H, d), 2.84 (1H,m), 3.71 (3H, s), 6.27 (2H, m), 6.95 (1H, d).

Example 31 trans-[4-(2,4-Dihydroxyphenyl)cyclohexyl]acetic Acid

To a round 25 ml bottomed flask containing trans-methyl[4-(2,4-dihydroxyphenyl)cyclohexyl]acetate (60 mg, 0.23 mmol) and water(4 ml) was added sodium hydroxide (32 mg, 0.78 mmol) and the solutionheated to 40° C. for 1 hr. The solution was poured into a separatingfunnel containing ethyl acetate (15 ml) and water (10 ml). To theaqueous layer was then added aqueous hydrochloric acid (10 ml, 1.0M) andethyl acetate (20 ml). The layers were separated and the aqueous layerextracted with ethyl acetate (3×10 ml). The combined organic extractswere washed with brine (15 ml), dried over magnesium sulfate, filteredand concentrated in vacuo affording the title compound (34 mg, 60%) as asolid. m/z (ES⁺) 251 (M+H⁺); δ_(H)(CD₃OD) 1.20 (2H, m), 1.48 (2H, m),1.89 (4H, m), 2.25 (2H, d), 2.81 (1H, m), 6.27 (2H, m), 6.91 (1H, m).

Example 32 cis-[4-(2,4-Dihydroxyphenyl)cyclohexyl]acetic Acid

To a round 25 ml bottomed flask containing cis-methyl[4-(2,4-dihydroxyphenyl)cyclohexyl]acetate (10 mg, 0.038 mmol) and water(4 ml) was added sodium hydroxide (5 mg, 0.13 mmol) and the solutionheated to 40° C. for 1 hr. The solution was poured into a separatingfunnel containing ethyl acetate (15 ml) and water (10 ml). To theaqueous layer was then added aqueous hydrochloric acid (10 ml, 1.0M) andethyl acetate (20 ml). The layers were separated and the aqueous layerextracted with ethyl acetate (3×10 ml). The combined organic extractswere washed with brine (15 ml), dried over magnesium sulfate, filteredand concentrated in vacuo affording the title compound (5 mg, 55%) as asolid. m/z (ES⁺) 251 (M+H⁺); δ_(H)(CD₃OD) 1.61-1.77 (8H, m), 2.30 (1H,m), 2.49 (2H, d), 2.84 (1H, m), 6.27 (2H, m), 6.96 (1H, d).

Example 33 cis/trans-[4-(2,4-Dihydroxyphenyl)cyclohexyl]acetic Acid

To a round bottomed flask equipped with magnetic stirrer was added{4-[2,4-dihydroxyphenyl]cyclohexylidene}acetic acid (50 mg, 0.20 mmol)and ethanol (15 ml). To the stirred solution was added palladium(catalytic amount, 10% on activated carbon) in one portion. The reactionvessel was evacuated and then placed under an atmosphere of hydrogen.This was repeated ten times and then stirred for 17 hr under a hydrogenatmosphere at room temperature. The reaction mixture was filteredthrough a celite plug, washing with ethanol. The solvent was removed invacuo to give the title compound (50 mg, 100%) as a pale yellow oil. m/z(ES⁺) 251 (M+H⁺); δ_(H)(CD₃OD) 1.33-1.91 (9H, m), 2.30 (2H, m), 2.81(1H, m), 6.28 (2H, m), 6.94 (1H, m).

Example 34 cis/trans-[4-(2,4-Dihydroxyphenyl)cyclohexyl]acetonitrile

To a round bottomed flask equipped with magnetic stirrer was added{4-[2,4-bis(methoxymethoxy)phenyl]cyclohexylidene}acetonitrile (408 mg,1.3 mmol) and methanol (20 ml). The resulting solution was heated toreflux temperature and aqueous hydrochloric acid (20 ml, 1.0M) wasadded. The solution was heated for 1 hr then cooled and saturatedaqueous sodium bicarbonate solution (50 ml) added. The mixture waspartitioned between ethyl acetate (100 ml) and water (20 ml) and theaqueous layer was extracted with ethyl acetate (2×20 ml). The combinedorganic layers were washed with brine (20 ml), dried over magnesiumsulfate, filtered and concentrated in vacuo affording an oil. To a 50 mlround bottomed flask equipped with magnetic stirrer was added crude[4-(2,4-dihydroxyphenyl)cyclohexylidene]acetonitrile (ca. 224 mg, 0.98mmol) and ethanol (15 ml). To the stirred solution was added palladium(catalytic amount, 10% on activated carbon) in one portion. The reactionvessel was evacuated and then placed under a hydrogen atmosphere. Thisprocess was repeated 10 times before leaving the reaction mixture undera hydrogen atmosphere. Vigorous stirring was continued for 17 hr, thenthe reaction mixture was filtered through celite washing with methanol.The solvent was removed under reduced pressure and the residue waspurified via flash column chromatography (SiO₂, ethyl acetate/petroleumether, 1:1, v/v), furnishing the title compound (226 mg, 80% over 2steps) as a colourless oil. m/z (ES⁺) 232 (M+H⁺); δ_(H)(CD₃OD) 1.31 (1H,m), 1.52 (1H, m), 1.67 (1H, m), 1.77 (0.5H, m), 1.83 (1H, m), 1.92 (2H,m), 1.98 (2H, m), 2.22 (0.5H), 2.44 and 2.67 (2H, d), 2.84 (1H, m), 6.28(2H, m), 6.96 (1H, m).

Example 35 cis/trans-4-[4-(2-Aminoethyl)cyclohexyl]-1,3-benzenediolHydrochloride

(Cis/trans)-[4-(2,4-dihydroxyphenyl)cyclohexyl]acetonitrile (214 mg,0.95 mmol), ethanol (25 ml) and chloroform (1 ml) were placed in a bomband platinum (IV) oxide (25 mg, 0.11 mmol) was added. The bomb wasplaced in a high pressure hydrogenation apparatus and shaken for 4 hr atca. 50 psi under a hydrogen atmosphere. The reaction mixture wasfiltered through a celite plug, washing with methanol (30 ml). Thesolvents were removed in vacuo and the residue was washed with ethylacetate (3×10 ml) to yield the title compound (161 mg, 64%) as a yellowoil. m/z (ES⁺) 236 (M+H⁺); δ_(H)(CD₃OD) 1.08-1.93 (11H, m), 2.79 and2.97 (1H, m), 2.99 (2H, m), 6.22 (2H, m), 6.88 (1H, m).

Example 36 (±)-4-(3,3-Difluorocyclohexyl)-1,3-benzenediol

A mixture of(±)-1-(3,3-difluorocyclohexyl)-2,4-bis(methoxymethoxy)benzene (30 mg),methanol (2 ml) and acidic ion exchange resin (200 mg) was heated underreflux for 4 h. The reaction mixture was filtered and the resin waswashed with methanol. The combined filtrate and washings were evaporatedin vacuo and the crude residue was purified by preparative HPLC to givethe title compound as a solid (5 mg, 23%). δ_(H)(CD₃OD) 1.2-2.2 (8H, m),3.08 (1H, m), 6.23-6.27 (2H, m), 6.87 (1H, d); m/z (ES⁻) 287(M−1+AcOH)⁻.

Example 37 (±)-3-(2,4-Dihydroxyphenyl)cyclohexanecarboxamide

(±)-3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexanecarboxamide (22 mg),methanol (2 ml) and acidic ion exchange resin (300 mg) were heated toreflux for 5 hr. The reaction mixture was filtered and the resin waswashed with methanol. The combined filtrate and washings were evaporatedin vacuo and the crude residue was purified by preparative HPLC to givethe title compound as a white solid (5 mg, 31%). δ_(H)(CD₃OD) 1.45-1.82(6H, m), 2.07-2.19 (2H, m), 2.62-2.69 (1H, m), 3.00-3.09 (1H, m),6.20-6.28 (2H, m), 6.89 (1H, d); m/z (ES⁺) 236 (M+H)⁺.

Example 38 (±)-3-(2,4-Dihydroxyphenyl)-N-hydroxycyclohexanecarboxamide

(±)-3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexyl}methanol (25 mg),methanol (2 ml) and acidic ion exchange resin (300 mg) were heated underreflux for 4 hr. The reaction mixture was filtered and the resin waswashed with methanol. The combined filtrate and washings were evaporatedin vacuo and the crude residue was purified by preparative HPLC to givethe title compound as a solid (5 mg, 27%). δ_(H)(CD₃OD) 1.28-2.40 (8H,m), 2.08-2.20 (0.5H, m), 2.78-2.94 (1H, m), 3.60-3.72 (2H, m), 6.20-6.28(2H, m), 6.80-6.90 (1H, m); m/z (ES⁻) 250 (M−H)⁻.

Example 39 (±)-3-(2,4-Dihydroxyphenyl)-N-ethylcyclohexanecarboxamide

(±)-3-[2,4-Bis(methoxymethoxy)phenyl]-N-ethylcyclohexanecarboxamide (25mg), methanol (2 ml) and acidic ion exchange resin (300 mg) were heatedto reflux for 4 hr. The reaction mixture was filtered and the resin waswashed with methanol. The combined filtrate and washings were evaporatedin vacuo and the crude residue was purified by preparative HPLC tofurnish the title compound as a solid (2 mg, 12%). δ_(H)(CD₃OD) 1.80(3H, t), 1.30-1.60 (4H, m), 1.74-1.94 (4H, m), 2.26-2.36 (1H, m),2.82-2.92 (1H, m), 3.16 (2H, q), 6.21-6.26 (2H, m), 6.88 (1H, d); m/z(ES⁺) 264 (M+H)⁺.

Example 40 (±)-4-[3-Hydroxy-3-(hydroxymethyl)cyclohexyl]-1,3-benzenediol

(±)-3-[2,4-Bis(methoxymethoxy)phenyl]-1-(hydroxymethyl)cyclohexanol (29mg), methanol (2 ml) and acidic ion exchange resin (300 mg) were heatedunder reflux for 3 hr. The reaction mixture was filtered and the resinwas washed with methanol. The combined filtrate and washings wereevaporated in vacuo and the crude residue was purified by preparativeHPLC to furnish the title compound as a cream solid (5 mg, 24%).δ_(H)(CD₃OD) 1.20-2.00 (8H, m), 2.89 (1H, tt), 3.61 (1H, d), 3.69 (1H,d), 6.20-6.26 (2H, m), 6.90 (1H, d); m/z (ES⁻) 237 (M−H)⁻.

Example 41 (±)-N-[3-(2,4-dihydroxyphenyl)cyclohexyl]acetamide

(±)-N-{3-[2,4-bis(methoxymethoxy)phenyl]cyclohexyl}acetamide (20 mg),methanol (2 ml) and acidic ion exchange resin (300 mg) were heated underreflux for 3 hr. The reaction mixture was filtered and the resin waswashed with methanol. The combined filtrate and washings were evaporatedin vacuo and the crude residue was purified by preparative HPLC tofurnish the title compound as a solid (5 mg, 34%). δ_(H)(CD₃OD) 1.10-200(1H, m), 2.90 (0.3H, tt), 3.08 (0.7H, tt), 3.70-380 (0.3H, m), 4.16(0.7H, m), 6.20-6.26 (2H, m), 6.84-6.90 (1H, m); m/z (ES⁺) 250 (M+H)⁺.

Example 42 trans-4-(2,4-Dihydroxyphenyl)cyclohexyl)4-(dimethylamino)benzoate

A mixture oftrans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl4-(dimethylamino)benzoate (18 mg), methanol (5 ml) and Amberlystfluoride resin (0.5 g) were stirred at room temperature for 24 hr. Thereaction mixture was filtered, and the filtrate was evaporated in vacuo.The residue was purified by flash column chromatography (SiO₂, ethylacetate/petrol, 2:3 v/v) to give the title compound as a white solid (8mg, 73%). δ_(H)(CD₃OD) 1.56-1.70 (4H, m), 1.88-1.94 (2H, m), 2.16-2.20(2H, m), 2.80-2.90 (1H, m), 3.00 (6H, s), 6.20-2.26 (2H, m), 6.70 (2H,d), 6.92 (1H, d), 7.62 (2H, d); m/z (ES⁺) 356 (M+H)⁺.

Example 43 cis/trans-4-(2,4-Dihydroxyphenyl)cyclohexanecarboxylic Acid

Tetrabutylammonium fluoride (0.12 ml) was added to a stirred solution of4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanecarboxylicacid (22 mg) in tetrahydrofuran (1 ml) at room temperature under argon.After 24 hr, the reaction mixture was partitioned between ethyl acetate(30 ml) and water (30 ml). The layers were separated and the aqueouslayer was extracted with ethyl acetate (2×30 ml). The combined organicextracts were dried over magnesium sulfate and evaporated in vacuo. Theresidue was purified by flash column chromatography (SiO₂, ethylacetate/petrol, 7:1 v/v, <1% acetic acid) to give the title compound asan orange solid (10 mg, 89%). δ_(H)(CD₃OD) 1.40-1.65 (4H, m), 1.88-1.95(2H, m), 2.06-2.14 (2H, m), 2.35 (1H, tt), 2.82 (1H, it), 6.25-6.30 (2H,m), 6.90 (1H, d); m/z (ES⁻) 235 (M−H)⁻.

Example 44 trans-4-(2,4-Dihydroxyphenyl)cyclohexyl Ethylcarbamate

A mixture oftrans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylethylcarbamate (18 mg), methanol (10 ml) and Amberlyst fluoride resin(0.3 g) were stirred at room temperature for 24 hr. The reaction mixturewas filtered, and the filtrate was evaporated in vacuo. The residue waspurified by flash column chromatography (SiO₂, ethyl acetate/petrol, 1:3v/v) to give the title compound as a white solid (24 mg, 87%).δ_(H)(CD₃OD) 1.10 (3H, t), 1.40-1.60 (4H, m), 1.80-1.90 (2H, m),2.00-2.10 (2H, m), 2.72-2.80 (1H, m), 3.10 (2H, t), 4.50-4.60 (1H, m),6.20-6.26 (2H, m), 6.88 (1H, d); m/z (ES⁺) 280 (M+H)⁺.

Example 45 trans-4-(2,4-Dihydroxyphenyl)cyclohexyl Cyclohexylcarbamate

A mixture oftrans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylcyclohexylcarbamate (28 mg), methanol (10 ml) and Amberlyst fluorideresin (0.3 g) were stirred at room temperature for 72 hr. The reactionmixture was filtered and the filtrate was evaporated in vacuo. Theresidue was purified by flash column chromatography (SiO₂, ethylacetate/petrol, 1:3 v/v) to give the title compound as a white solid (6mg, 36%); δ_(H)(CD₃OD) 1.10-2.12 (18H, m), 2.70-2.82 (1H, m), 4.46-4.60(1H, m), 6.18-6.30 (2H, m), 6.80-6.92 (1H, m); m/z (ES⁺) 334 (M+H)⁺.

General Procedure for Preparation for Examples 46-53

A round bottom flask equipped with stirrer bar was charged withtrans-4-(2,4-dihydroxyphenyl)cyclohexanol (208 mg, 1 mmol),dichloromethane (20 ml), triethylamine (1.4 ml, 10 mmol) and4-dimethylaminopyridine (catalytic amount). The flask was purged withargon and the appropriate acid chloride (5 mmol) added dropwise withstirring. The reaction mixture was then set aside for 24 hr. Thereaction mixture was then diluted with dichloromethane (20 ml) andwashed successively with hydrochloric acid (10 ml of a 2M aqueoussolution), saturated aqueous sodium hydrogen carbonate (10 ml), brine(10 ml), dried over magnesium sulfate and evaporated in vacuo. Theresulting residue was suspended in a mixture of tetrahydrofuran (20 ml)and methanol (5 ml) and cesium carbonate (685 mg, 2.1 mmol) in water (5ml) was added. The reaction mixture was warmed at 50° C. until TLCanalysis indicated complete conversion to the title compound. Thereaction solution was concentrated to approximately one quarter itsoriginal volume, diluted with water (10 ml) and extracted with ethylacetate (3×10 ml). The combined organic extracts were washed with brine,dried over magnesium sulfate and evaporated in vacuo. The residue waspurified using flash column chromatography (SiO₂, ethyl acetate/petrol).

Example 46 trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-tert-butylbenzoate

The title compound was isolated as an oil (180 mg, 49%), as described inthe general procedure above. δ_(H) (d⁴-MeOH) 1.34 (9H, s), 1.54-1.71(4H, m), 1.87-1.94 (2H, m), 2.14-2.21 (2H, m), 2.86 (1H, m), 4.95 (1H,m), 6.24 (1H, dd), 6.27 (1H, d), 6.91 (1H, d), 7.50 (2H, d), 7.94 (2H,d); m/z (ES⁺) 369 (M+H)⁺.

Example 47 trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-fluorobenzoate

The title compound was isolated as a white solid (133 mg, 40%), asdescribed in the general procedure above. δ_(H) (d⁴-MeOH) 1.54-1.72 (4H,m), 1.86-1.95 (2H, m), 2.13-2.20 (2H, m), 2.86 (1H, m), 4.96 (1H, m),6.24 (1H, dd), 6.26 (1H, d), 6.91 (1H, d), 7.18 (2H, m), 8.06 (2H, m);m/z (ES⁺) 331 (M+H)⁺.

Example 48 trans-4-(2,4-Dihydroxyphenyl)cyclohexyl4-trifluoromethylbenzoate

The title compound was isolated as a white solid (261 mg, 69%), asdescribed in the general procedure above. δ_(H) (d⁴-MeOH) 1.54-1.74 (4H,m), 1.88-1.96 (2H, m), 2.16-2.24 (2H, m), 2.88 (1H, m), 5.01 (1H, m),6.25 (1H, dd), 6.28 (1H, d), 6.91 (1H, d), 7.79 (2H, m), 8.17 (2H, m);m/z (ES⁺) 381 (M+H)⁺.

Example 49 trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-methoxybenzoate

The title compound was isolated as a white solid (248 mg, 73%), asdescribed in the general procedure above. δ_(H) (d⁴-MeOH) 1.54-1.74 (4H,m), 1.88-1.96 (2H, m), 2.16-2.24 (2H, m), 2.88 (1H, m), 5.01 (1H, m),6.25 (1H, dd), 6.28 (1H, d), 6.91 (1H, d), 7.79 (2H, m), 8.17 (2H, m);m/z (ES⁺) 381 (M+H)⁺.

Example 50 trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-methylbenzoate

The title compound was isolated as a white solid (75 mg, 23%), asdescribed in the general procedure above. δ_(H) (d⁴-MeOH) 1.53-1.75 (4H,m), 1.89-1.96 (2H, m), 2.12-2.23 (2H, m), 2.40 (3H, s), 2.86 (1H, m),4.98 (1H, m), 6.25 (2H, m), 6.92 (1H, d), 7.25 (2H, m), 7.90 (2H, m);m/z (ES⁺) 653 (2M+H)⁺.

Example 51 trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 4-chlorobenzoate

The title compound was isolated as a white solid (230 mg, 67%), asdescribed in the general procedure above. δ_(H) (d⁴-MeOH) 1.54-1.75 (4H,m), 1.88-1.97 (2H, m), 2.15-2.24 (2H, m), 2.87 (1H, m), 4.98 (1H, m),6.22-6.29 (2H, m), 6.92 (1H, d), 7.49 (2H, d), 8.00 (2H, d); m/z (ES⁺)347 (M+H)⁺.

Example 52 trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 3,4-dimethylbenzoate

The title compound was isolated as a white solid (84 mg, 25%), asdescribed in the general procedure above. δ_(H) (d⁴-MeOH) 1.55-1.72 (4H,m), 1.88-1.95 (2H, m), 2.14-2.21 (2H, m), 2.32 (3H, s), 2.33 (3H, s),2.85 (1H, m), 4.95 (1H, m), 6.22-6.28 (2H, m), 6.92 (1H, d), 7.21 (1H,d), 7.75 (1H, d), 7.79 (1H, s); m/z (ES⁺) 341 (M+H)⁺.

Example 53 trans-4-(2,4-Dihydroxyphenyl)cyclohexyl 3,4-dichlorobenzoate

The title compound was isolated as a white solid (304 mg, 80%), asdescribed in the general procedure above. δ_(H) (d⁴-MeOH) 1.56-1.78 (4H,m), 1.86-1.98 (2H, m), 2.12-2.23 (2H, m), 2.84 (1H, m), 4.99 (1H, m),6.20-6.30 (2H, m), 6.92 (1H, d), 7.64 (1H, d), 7.92 (1H, d), 8.12 (1H,s); m/z (ES⁻) 379 (M−H)⁻.

Example 54 trans-4-[4-(Phenylsulfanyl)cyclohexyl]-1,3-benzenediol

A round bottom flask containing thiophenol (30 μl, 0.29 mmol), cesiumfluoride (44 mg, 0.29 mmol) and N,N-dimethylformamide (3 ml) was warmedat 40° C. for 1 hr. To this was addedcis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylmethanesulfonate (100 mg, 0.19 mmol) in N,N-dimethylformamide (1 ml) andthe reaction mixture stirred at 50° C. for 18 hr. The reaction mixturewas poured into saturated aqueous sodium hydrogen carbonate (10 ml) andextracted with ethyl acetate (3×20 ml). The combined organic extractswere washed with brine (10 ml), dried over magnesium sulfate andconcentrated in vacuo. Purification via flash column chromatography(SiO₂, ethyl acetate/petrol, 1:3) afforded the title compound (23 mg,40%) as an off-white solid. δ_(H) (d⁴-MeOH) 1.40-1.57 (4H, m), 1.82-1.90(2H, m), 2.04-2.16 (2H, m), 2.80 (1H, m), 3.13 (1H, m), 6.19-6.28 (2H,m), 6.88 (1H, d), 7.23 (1H, m), 7.30 (2H, m), 7.40 (2H, m); m/z (ES⁺)301 (M+H)⁺.

Example 55 trans-4-[4-(Phenylsulfonyl)cyclohexyl]-1,3-benzenediol

A round bottom flask containingtrans-4-[4-(phenylsulfanyl)cyclohexyl]-1,3-benzenediol (18 mg, 0.06mmol) and dichloromethane (2 ml) was cooled to 0° C. andmeta-chloroperbenzoic acid (50-60%, 41 mg, 0.24 mmol) was added withstirring. After 30 min at this temperature the reaction mixture waspoured into saturated sodium thiosulfate solution (5 ml) and partitionedbetween saturated aqueous sodium hydrogen carbonate (10 ml) anddichloromethane (10 ml). The aqueous phase was further extracted withdichloromethane (2×10 ml) and the combined organic extracts were washedwith brine, dried over magnesium sulfate and concentrated in vacuo.Purification via flash column chromatography (SiO₂, ethylacetate/petrol, 30:70) afforded the title compound (6 mg, 30%) as anoff-white solid. δ_(H) (d⁴-MeOH) 1.40-1.62 (4H, m), 1.88-1.95 (2H, m),2.05-2.13 (2H, m), 2.72 (1H, m), 3.18 (1H, m), 6.08-6.13 (2H, m), 6.82(1H, d), 7.64 (2H, m), 7.75 (1H, m), 7.90 (2H, m); m/z (ES⁺) 333 (M+H)⁺.

Example 56 [4-(2,4-Dihydroxyphenyl)cyclohexyl]methyl Propionate

A mixture of[4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]methylpropionate (110 mg), methanol (10 ml) and Amberlyst fluoride resin (0.4g) were stirred at room temperature for 72 hr. The reaction mixture wasfiltered, and the filtrate was evaporated in vacuo. The residue waspurified by flash column chromatography (SiO₂, ethyl acetate/petrol, 1:2v/v) to give the title compound as a cream solid and a mixture ofdiastereoisomers (44 mg, 73%). δ_(H)(CDCl₃) 1.17 (3H, t), 1.38-2.14 (9H,m), 2.34-2.40 (2H, q), 2.64-2.80 (1H, m), 3.96 (0.6H, d), 4.20 (0.4H,d), 5.10-5.24 (2H, m), 6.28-6.33 (1H, m), 6.36-6.40 (1H, m), 6.98 (1H,dd); m/z (ES⁺) 279 (M+H)⁺.

Examples 57 and 58 Diastereoisomers of Ethyl4-(2,4-dihydroxyphenyl)-1-hydroxycyclohexane Carboxylate

A solution of one isomer of ethyl4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-hydroxycyclohexanecarboxylate(25 mg, 0.05 mmol) in methanol (2 ml) was stirred rapidly with AmberlystA-26 (100 mg) for 18 hr. After this time the reaction mixture wasfiltered. The resin was then stirred rapidly for 1 hr in a solution ofmethanol (2 ml) and glacial acetic acid (5 drops). The reaction mixturewas filtered and the combined filtrates concentrated in vacuo.Purification via flash column chromatography (SiO₂, ethylacetate/petrol, 2:1) afforded the title compound (3 mg, 21%) as a whitesolid. δ_(H) (d⁴-MeOH) 1.29 (3H, t), 1.61-1.69 (2H, m), 1.73-1.98 (6H,m), 2.81-2.90 (1H, m), 4.18 (2H, q), 6.21-6.27 (2H, m), 6.91 (1H, d);m/z (ES⁻) 279 (M−H)⁻.

A solution of the other isomer of ethyl4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-hydroxycyclohexanecarboxylate (25 mg, 0.05 mmol) inmethanol (2 ml) was stirred rapidly with Amberlyst A-26 (100 mg) for 18hr. After this time the reaction mixture was filtered. The resin wasthen stirred rapidly for 1 hr in a solution of methanol (2 ml) andglacial acetic acid (5 drops). The reaction mixture was filtered and thecombined filtrates concentrated in vacuo. Purification via flash columnchromatography (SiO₂, ethyl acetate/petrol, 2:1) afforded the titlecompound (5 mg, 34%) as a white solid. δ_(H) (d⁴-MeOH) 1.22 (3H, t),1.40-1.54 (4H, m), 1.63-1.74 (2H, m), 2.18-2.25 (2H, m), 2.68-2.78 (1H,m), 4.14 (2H, q), 6.11 (1H, dd), 6.15 (1H, d), 6.71 (1H, d); m/z (ES⁻)279 (M−H)⁻.

Example 59 Cis/trans-4-[4-(hydroxyamino)cyclohexyl]-1,3, benzenediol

To a stirred solution of 4-(2,4-dihydroxyphenyl)cyclohexanone oxime (90mg, 0.41 mmol) in acetic acid (3 ml) was added sodium cyanoborohydride(28 mg, 0.45 mmol) in one portion. After stirring for 16 hr, a furtherportion of sodium cyanoborohydride (28 mg) was added and stirringcontinued for a further 48 hr. The reaction mixture was poured into amixture of water (3 ml) and ethyl acetate (25 ml) and stirred for 30min. The solution was partitioned, and the aqueous layer furtherextracted with ethyl acetate (5×10 ml). The combined organics werewashed with brine (15 ml), dried over magnesium sulfate and concentratedin vacuo. Purification by HPLC afforded the title compound as a palepink solid (62 mg, 68%). δ_(H)(CD₃OD) 1.57-1.77 (3H, m), 1.78-1.84 (1H,m), 1.90-2.09 (2H, m), 2.27-2.12 (2H, m), 2.87 (0.6H, m), 3.03 (0.4H,m), 3.58 (0.4H, m), 3.68 (0.6H, m), 6.25-6.32 (2H, m), 6.92 (0.6H, d),6.99 (0.4H, d), m/z (ES⁻) 222 (M−H)⁻.

Example 60 Trans-4-[4-(methoxyamino)cyclohexyl]-1,3, benzenediol

To a stirred solution of O-methyl-4-(2,4-dihydroxyphenyl)cyclohexanoneoxime (18 mg, 0.076 mmol) in acetic acid (1 ml) was added sodiumcyanoborohydride (25 mg, 0.4 mmol) in one portion. After stirringovernight the reaction mixture was partitioned between water (10 ml) andethyl acetate (10 ml). The aqueous layer was further extracted withethyl acetate (10 ml) and the combined organic phases were washed withsaturated sodium hydrogen carbonate solution (10 ml), dried overmagnesium sulfate and concentrated in vacuo. Purification by flashcolumn chromatography (SiO₂, ethyl acetate/petrol 2:3) afforded thetitle compound as a solid (12 mg, 66%). δ_(H)(CDCl₃) 1.13-1.26 (2H, m),1.30-1.45 (2H, m), 1.80-1.89 (2H, m), 1.90-2.00 (2H, m), 2.68-2.78 (1H,m), 2.80-2.90 (1H, m), 3.49 (3H, s), 6.19 (1H, d), 6.24 (1H, dd), 6.86(1H, d); m/z (ES⁺) 279 (MH+CH₃CN)⁺.

All patents, patent applications, and publications cited above areincorporated herein by reference in their entirety.

The present invention is not to be limited in scope by the specificembodiments described herein, which are intended as single illustrationsof individual aspects of the invention, and functionally equivalentmethods and components are within the scope of the invention. Indeed,various modifications of the invention, in addition to those shown anddescribed herein will become apparent to those skilled in the art fromthe foregoing description. Such modifications are intended to fallwithin the scope of the appended claims.

What is claimed is:
 1. A compound of formula l:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is a(C₃-C₈)cycloalkyl ring or (C₅-C₈)cycloalkenyl ring, wherein either thecycloalkyl ring or cycloalkenyl ring is substituted by one to threesubstituents independently selected from the group consisting of cyano;halo; (C₁-C₆)alkyl; aryl; (C₂-C₉)heterocycloalkyl; (C₂-C₉)heteroaryl;aryl(C₁-C₆)alkyl-; ═O; ═CHO(C₁-C₆)alkyl; amino; hydroxy; (C₁-C₆)alkoxy;aryl(C₁-C₆)alkoxy-; (C₁-C₆)acyl; (C₁-C₆)alkylamino-;aryl(C₁-C₆)alkylamino-; amino(C₁-C₆)alkyl-; (C₁-C₆)alkoxy-CO—NH—;(C₁-C₆)alkylamino-CO—; (C₂-C₆)alkenyl; (C₂-C₆)alkynyl;hydroxy(C₁-C₆)alkyl-; (C₁-C₆)alkoxy(C₁-C₆)alkyl-;(C₁-C₆)acyloxy(C₁-C₆)alkyl-; nitro; cyano(C₁-C₆)alkyl-;halo(C₁-C₆)alkyl-; nitro(C₁-C₆)alkyl-; trifluoromethyl;trifluoromethyl(C₁-C₆)alkyl; (C₁-C₆)acylamino-;(C₁-C₆)acylamino(C₁-C₆)alkyl-; (C₁-C₆)alkoxy(C₁-C₆)acylamino-;amino(C₁-C₆)acyl-; amino(C₁-C₆)acyl(C₁-C₆)alkyl-;(C₁-C₆)alkylamino(C₁-C₆)acyl-; ((C₁-C₆) alkyl)₂amino(C₁-C₆)acyl-;—CO₂R²; —(C₁-C₆)alkyl-CO₂R²; —C(O)N(R²)₂; —(C₁-C₆)alkyl-C(O)N(R²)₂;R²ON═; R²ON═(C₁-C₆)alkyl-; R²ON═CR²(C₁-C₆)alkyl-; —NR²(OR²);—(C₁-C₆)alkyl-NR²(OR²); —C(O)(NR²R²); —(C₁-C₆)alkyl-C(O)(NR²OR²);—S(O)_(m)R²; wherein each R² is independently selected from hydrogen,(C₁-C₆)alkyl, aryl, or aryl(C₁-C₆)alkyl-; R³C(O)O—, wherein R³ is(C₁-C₆)alkyl, aryl, or aryl(C₁-C₆)alkyl-; R³C(O)O—(C₁-C₆)alkyl-;R⁴R⁵N—C(O)—O—; R⁴R⁵NS(O)₂—; R⁴R⁵NS(O)₂(C₁-C₆)alkyl-; R⁴S(O)₂R⁵N—;R⁴S(O)₂R⁵N(C₁-C₆)alkyl-; wherein m is 0, 1 or 2, and R⁴ and R⁵ are eachindependently selected from hydrogen or (C₁-C₆)alkyl; —C(═NR⁶)(N(R⁴)₂);or —(C₁-C₆)alkyl-C(═NR⁶)(N(R⁴)₂) wherein R⁶ represents OR² or R² whereinR² is defined as above; with the proviso that the cycloalkenyl ring isnot aromatic; with the proviso that R¹ must be substituted by at leastone of R³C(O)O—, R³C(O)O—(C₁-C₆)alkyl-, R²ON═, R²ON═(C₁-C₆)alkyl-, R²ON═CR²(C₁-C₆)alkyl-, —NR²(OR²), R⁴R⁵NS(O)₂—, R⁴R⁵NS(O)₂(C₁-C₆)alkyl-,R⁴S(O)₂R⁵N—, or R⁴S(O)₂R⁵N(C₁-C₆)alkyl-; with the proviso that when R¹is only substituted by one of R ²ON═, then R² cannot be hydrogen.
 2. Thecompound of claim 1, wherein R¹ is a cyclohexyl or cyclohexenyl ringsubstituted at the 3- or 4-position, or a cyclopentyl or cyclopentenylring substituted at the 3-position.
 3. The compound of claim 1, whereinR¹ is monosubstituted.
 4. The compound of claim 1, wherein R¹ isdisubstituted.
 5. The compound of claim 1, wherein R¹ is substituted byat least one of R³C(O)O— or R³C(O)O—(C₁-C₆)alkyl-.
 6. The compound ofclaim 1, wherein R¹ is substituted by at least one of R² ON═,R²ON═(C₁-C₆)alkyl-, or R²ON═CR²(C₁-C₆)alkyl-.
 7. The compound of claim1, wherein R¹ is substituted by at least one of —NR²(OR²).
 8. Thecompound of claim 1, wherein R¹ is substituted by at least one ofR⁴R⁵NS(O)₂—, R⁴R⁵NS(O)₂(C₁-C₆)alkyl-, R⁴S(O)₂R⁵N—, orR⁴S(O)₂R⁵N(C₁-C₆)alkyl-.
 9. The compound of claim 1, wherein R¹ issubstituted by at least one of R⁴S(O)₂R⁵N— or R⁴S(O)₂R⁵N(C₁-C₆)alkyl-.10. The compound of claim 1, wherein R¹ is a (C₃-C₈)cycloalkyl ring or(C₅-C₈) cycloalkenyl ring, wherein either the cycloalkyl ring orcycloalkenyl ring is substituted by one of R³C(O)O—(C₁-C₆)alkyl-, R²ON,R²ON(C₁-C₆)alkyl-, R²ON═CR²(C₁-C₆)alkyl-, —NR₂(OR²), R⁴R⁵NS(O)2—,R⁴R⁵NS(O)2(C₁-C₆)alkyl-, R⁴S(O)₂R⁵N—, or R⁴S(O)₂R⁵N(C₁-C⁶)alkyl-. 11.The compound of claim 10, wherein R¹ is a (C₃-C₈)cycloalkyl ring or(C₅-C₈) cycloalkenyl ring, wherein either the cycloalkyl ring orcycloalkenyl ring is substituted by one of R³C(O)O—(C₁-C₆)alkyl-, R²ON,or R⁴S(O)₂R⁵N—.
 12. The compound of claim 10, wherein R¹ is substitutedby R³C(O)O—(C₁-C₆)alkyl-.
 13. The compound of claim 10, wherein R¹ issubstituted by R²ON═, R²ON═(C₁-C₆)alkyl-, or R²ON═CR²(C₁-C₆)alkyl-. 14.The compound of claim 10, wherein R¹ is substituted by R²ON═.
 15. Thecompound of claim 10, wherein R¹ is substituted by —NR²(OR²).
 16. Thecompound of claim 10, wherein R¹ is substituted by R⁴R⁵NS(O)₂—,R⁴R⁵NS(O)₂(C₁-C₆)alkyl-, R⁴S(O)₂R⁵N(C₁-C₆)alkyl-.
 17. The compound ofclaim 1, wherein R¹ is substituted by R⁴S(O)₂R⁵N— orR⁴S(O)₂R⁵N(C₁-C₆)alkyl-.
 18. The compound of claim 1, wherein the(C₂-C₉)heterocycloalkyl substituent is a group of the formula:

wherein m is 0, 1 or 2, and Z is CH₂, NR, O, S, SO, or SO_(2.)
 19. Thecompound of claim 1 selected from the group consisting of:O-Benzyl-4-(2,4-dihydroxyphenyl)cyclohexanone oxime;(±)-N-[3-(2,4-Dihydroxyphenyl)cyclohexyl]methanesulfonamide;(±)-O-Methyl-3-(2,4-dihydroxyphenyl)cyclohexanone oxime;(±)-O-Benzyl-3-(2,4-dihydroxyphenyl)cyclohexanone oxime; and apharmaceutically acceptable salt thereof.
 20. The compound of claim 1selected from the group consisting of:O-Methyl-4-(2,4-dihydroxyphenyl)cyclohexanone oxime;(±)-4-[3-(Hydroxyamino)cyclohexyl]-1,3-benzenediol;cis-N-[4-(2,4-Dihydroxyphenyl) cyclohexyl]-1-butanesulfonamide;trans-N-[4-(2,4-Dihydroxyphenyl) cyclohexyl]methanesulfonamidecis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]methanesulfonamide;[4-(2,4-Dihydroxyphenyl)cyclohexyl]methyl propionate;cis/trans-4-[4-(hydroxyamino)cyclohexyl]-1,3-benzenediol;trans-4-[4-(methoxyamino)cyclohexyl]-1,3-benzenediol; and apharmaceutically acceptable salt thereof.
 21. A topical pharmaceuticalcomposition for lightening skin or reducing the pigmentation of skin ina human, comprising a pharmaceutically acceptable carrier, and askin-lightening or pigmentation-reducing amount of a compound of formulaI:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is a(C₃-C₈)cycloalkyl ring or (C₅-C₈)cycloalkenyl ring, wherein either thecycloalkyl ring or cycloalkenyl ring is substituted by one to threesubstituents independently selected from the group consisting of cyano;halo; (C₁-C₆)alkyl; aryl; (C₂-C₉)heterocycloalkyl; (C₂-C₉)heteroaryl;aryl(C₁-C₆)alkyl-; ═O; ═CHO(C₁-C₆)alkyl; amino; hydroxy; (C₁-C₆)alkoxy;aryl(C₁-C₆)alkoxy-; (C₁-C₆)acyl; (C₁-C₆)alkylamino-;aryl(C₁-C₆)alkylamino-; amino(C₁-C₆)alkyl-; (C₁-C₆)alkoxy-CO—NH—;(C₁-C₆) alkylamino-CO—; (C₂-C₆)alkenyl; (C₂-C₆)alkynyl;hydroxy(C₁-C₆)alkyl-; (C₁-C₆)alkoxy(C₁-C₆)alkyl-;(C₁-C₆)acyloxy(C₁-C₆)alkyl-; nitro; cyano(C₁-C₆)alkyl-;halo(C₁-C₆)alkyl-; nitro(C₁-C₆)alkyl-; trifluoromethyl;trifluoromethyl(C₁-C₆)alkyl-; (C₁-C₆)acylamino-;(C₁-C₆)acylamino(C₁-C₆)alkyl-; (C₁-C₆)alkoxy(C₁-C₆)acylamino-;amino(C₁-C₆)acyl-; amino(C₁-C₆)acyl(C₁-C₆)alkyl-;(C₁-C₆)alkylamino(C₁-C₆)acyl-; ((C₁-C₆) alkyl)₂amino(C₁-C₆)acyl-;—CO₂R²; —(C₁-C₆)alkyl-CO₂R²; —C(O)N(R²)₂; —(C₁-C₆)alkyl-C(O)N(R²)₂;R²ON═; R²ON═(C₁-C₆)alkyl-; R²ON═CR²(C₁-C₆)alkyl-; —NR²(OR²);—(C₁-C₆)alkyl-NR²(OR²); —C(O)(NR²R²); —(C₁-C₆)alkyl-C(O)(NR²OR²);—S(O)_(m)R²; wherein each R² is independently selected from hydrogen,(C₁-C₆)alkyl, aryl, or aryl(C₁-C₆)alkyl-; R³C(O)O—, wherein R³ is(C₁-C₆)alkyl, aryl, or aryl(C₁-C₆)alkyl-; R³C(O)O—(C₁-C₆)alkyl-;R⁴R⁵N—C(O)—O—; R⁴R⁵NS(O)₂—; R⁴R⁵NS(O)₂(C₁-C₆)alkyl-; R⁴S(O)₂R⁵N—;R⁴S(O)₂R⁵N(C₁-C₆)alkyl-; wherein m is 0, 1 or 2, and R⁴ and R⁵ are eachindependently selected from hydrogen or (C₁-C₆)alkyl; —C(═NR⁶)(N(R⁴)₂);or —(C₁-C₆)alkyl-C(═NR⁶)(N(R⁴)₂) wherein R⁶ represents OR² or R² whereinR² is defined as above; with the proviso that the cycloalkenyl ring isnot aromatic; with the proviso that R¹ must be substituted by at leastone of R³C(O)O—, R³C(O)O—(C₁-C₆)alkyl-, R²ON═, R²ON═(C₁-C₆)alkyl-, R²ON═CR²(C₁-C₆)alkyl-, —NR²(OR²), R⁴R⁵NS(O)₂—, R⁴R⁵NS(O)₂(C₁-C₆)alkyl-,R⁴S(O)₂R⁵N—, or R⁴S(O)₂R⁵N(C₁-C₆)alkyl-.
 22. The composition of claim21, wherein R¹ of the compound is a cyclohexyl or cyclohexenyl ringsubstituted at the 3- or 4-position, or a cyclopentyl or cyclopentenylring substituted at the 3-position.
 23. The composition of claim 21,wherein R¹ of the compound is monosubstituted.
 24. The composition ofclaim 21, wherein R¹ of the compound is disubstituted.
 25. Thecomposition of claim 21, wherein R¹ of the compound is substituted by atleast one of R³C(O)O— or R³C(O)O—(C₁-C₆)alkyl-.
 26. The composition ofclaim 21, wherein R¹ of the compound is substituted by at least one ofR²ON═, R²ON═(C₁-C₆)alkyl-, or R²ON═CR²(C₁-C₆)alkyl-.
 27. The compositionof claim 21, wherein R¹ of the compound is substituted by at least oneof —NR²(OR²).
 28. The composition of claim 21, wherein R¹ of thecompound is substituted by at least one of R⁴R⁵NS(O)₂—,R⁴R⁵NS(O)₂(C₁-C₆)alkyl-, R⁴S(O)₂R⁵N—, or R⁴S(O)₂R⁵N(CG-C₆)alkyl-. 29.The composition of claim 21, wherein R¹ of the compound is substitutedby at least one of R⁴S(O)₂R⁵N— or R⁴S(O)₂R⁵N(C₁-C₆)alkyl-.
 30. Thecomposition of claim 21, wherein R¹ of the compound is a(C₃-C₈)cycloalkyl ring or (C₅-C₈)cycloalkenyl ring, wherein either thecycloalkyl ring or cycloalkenyl ring is substituted by one of R³C(O)O—,R³C(O)O—(C₁-C₆)alkyl-, R²ON═, R² ON═(C₁-C₆)alkyl-,R²ON═CR²(C₁-C₆)alkyl-, —NR²(OR²), R⁴R⁵NS(O)₂—, R⁴R⁵NS(O)₂(C₁-C₆)alkyl-,R⁴S(O)₂R⁵N—, or R⁴S(O)₂R⁵N(C₁-C₆)alkyl-.
 31. The composition of claim30, wherein R¹ of the compound is a (C₃-C₈)cycloalkyl ring or(C₅-C₈)cycloalkenyl ring, wherein either the cycloalkyl ring orcycloalkenyl ring is substituted by one of R³C(O)O—,R³C(O)O—(C₁-C₆)alkyl-, R²ON═, or R⁴S(O)₂R⁵N—.
 32. The composition ofclaim 30, wherein R¹ of the compound is substituted by R³C(O)O—(C₁-C₆)alkyl-.
 33. The composition of claim 30, wherein R¹ of thecompound is substituted by R²ON═, R²ON═(C₁-C₆)alkyl-, orR²ON═CR²(C₁-C₆)alkyl-.
 34. The composition of claim 30, wherein R¹ ofthe compound is substituted by R²ON═.
 35. The composition of claim 30wherein R¹ of the compound is substituted by —NR²(OR²).
 36. Thecomposition of claim 30, wherein R¹ of the compound is substituted byR⁴R⁵NS(O)₂—, R⁴R⁵NS(O)₂(C₁-C₆)alkyl-, R⁴S(O)₂R⁵N— orR⁴S(O)₂R⁵N(C₁-C₆)alkyl-.
 37. The composition of claim 30, wherein R¹ ofthe compound is substituted by R⁴S(O)₂R⁵N— or R⁴S(O)₂R⁵N(C₁-C₆)alkyl-.38. The composition of claim 21, wherein the (C₂-C₉)heterocycloalkylsubstituent is a group of the formula:

wherein m is 0, 1 or 2, and Z is CH₂, NR², O, S, SO, or SO₂.
 39. Thecomposition of claim 21, comprising a compound selected from the groupconsisting of: 4-(2,4-Dihydroxyphenyl)cyclohexanone oxime;O-Methyl-4-(2,4-dihydroxyphenyl)cyclohexanone oxime;O-Benzyl-4-(2,4-dihydroxyphenyl)cyclohexanone oxime;3-(2,4-Dihydroxyphenyl)-2-cyclohexen-1-one oxime;(±)-3-(2,4-Dihydroxyphenyl)cyclohexanone oxime;(±)-N-[3-(2,4-dihydroxyphenyl)cyclohexyl]methanesulfonamide;(±)-4-[3-(Hydroxyamino)cyclohexyl]-1,3-benzenediol;(±)-O-Methyl-3-(2,4-dihydroxyphenyl)cyclohexanone oxime;(±)-O-Benzyl-3-(2,4-dihydroxyphenyl)cyclohexanone oxime;3-(2,4-dihydroxyphenyl)-2-cyclopentenone oxime;(±)-3-(2,4-dihydroxyphenyl)cyclopentanone oxime; and a pharmaceuticallyacceptable salt thereof.
 40. The composition of claim 21, comprising acompound selected from the group consisting of:cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-1-butanesulfonamide;trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]methanesulfonamide;cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]methanesulfonamide;[4-(2,4-Dihydroxyphenyl)cyclohexyl]methyl propionate;cis/trans-4-[4-(hydroxyamino)cyclohexyl]-1,3-benzenediol;trans-4-[4-(methoxyamino)cyclohexyl]-1,3-benzenediol; and apharmaceutically acceptable salt thereof.
 41. The composition of claim21, wherein the skin-lightening or pigmentation-reducing effectiveamount of a compound of formula I is a tyrosinase-inhibiting effectiveamount of the compound.